Posted on Authorea 11 Sep 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.159986479.93555251 | This a preprint and has not been peer reviewed. Data may be preliminary. 5LX aha Fgr A.Tetr yLsicue ektin C 5-lipoxygenase leukotriene the includes through CysLTs (LTB acid immuno- term E arachidonic to in- The leukotriene response of bioactive 1A). in and release of inflammation (Figure the family of pathway following eicosanoid site (5-LOX) stimuli the the at nonimmunological of generated constituents and rapidly logical major are the They of lipid-mediators. one flammatory are (CysLTs) leukotrienes Cysteinyl INTRODUCTION metastasis cancer, inflammation, leukotrienes, Cysteinyl in anti-CysLTs the of on potential KEYWORDS update the recent on a and provides tumorigenesis also in It role the their expression. cancer. investigate explain and CysLTs of to help regulation of treatment postulated will effects their the been biological of progression have the knowledge cancer of that current overview mechanisms in an with Understanding molecular gives receptors along tumorigenesis. review their receptors, This increased therapy. and their with anti-cancer CysLTs and associated for of been receptors signaling orchestrate CysLTs CysLTs has role targeting mediators and of of the cancers lipid potential Upregulation underlying of these mechanisms several number how microenvironment. a molecular of determining pro-tumoral in pathophysiology the found in a the is interest promoting in production increased CysLTs through role and an metastasis central been and a has development play there tumor that Recently, mediators lipid diseases. inflammatory inflammatory are (CysLTs) leukotrienes Cysteinyl Abstract 2020 11, September 2 1 Saier cancer Lou in leukotrienes cysteinyl of role Emerging mohmsl oe yLshv la oei shaadalri hntsbthv lobe mlctdin implicated regulate gastrointestinal, 2011). been to cardiovascular, Funk, also (Haeggstr¨om including have and & diseases diseases but permeability inflammatory rhinitis neurodegenerative chronic vascular allergic and and pro- and increase immune, acute asthma bronchoconstriction many to in of role their known pathogenesis clear for also the a have are studied CysLTs tone. but primarly dendritic muscle by inflammation smooth are as CysLTs allergic well eosino- 2007). during as by Henderson, (monocytes/macrophages) particular perties lineages (in & monoblastic lineage (Peters-Golden and myeloblastic cells), three cells the mast contain from and leukocytes that basophils, by “leuko”cytes phils, biosynthesized by mainly generated are CysLTs lipids “leuko- The for term Samuelsson “tri-enes”. The by i.e. (GSH). ana- time glutathione bonds, 2011). to double that of Funk, conjugated (Haeggstr¨omconjugated at & substance lipids perfusates introduced slow-reacting as lung was CysLTs in of identified trienes” muscle later components smooth colleagues active of and contraction as Murphy and causes 1938 attraction that in (SRS-A) and phylaxis identified permeability, were vascular leukotrienes of Historically, stimulation muscle, (Hammarstr¨om, smooth 1983). leukocytes bronchial of of activation contraction as such INSERM U1033 INSERM 4 ,wihaecmol nw sluoree Ls.Luoree xii ies ilgcleffects biological diverse exhibit Leukotrienes (LTs). leukotrienes as known commonly are which ), 1 n lve Peyruchaud Olivier and 4 (LTE 4 ;te r tutrlydffrn rmluoreeA leukotriene from different structurally are they ); 2 1 4 (LTC 4 (LTA 4 ,luoreeD leukotriene ), 4 n ektin B4 leukotriene and ) 4 (LTD 4 ), Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. fmeodoii uha rnlcts(..nurpis oiohl,bspis,monocytes/macrophages, basophils), cells eosinophils, marrow-derived neutrophils, bone by (i.e. expressed granulocytes essentially as is 5-LOX such acids. origin amino into myeloid converted 675 is of of AA which consisting in protein biosynthesis CysLTs 78-kDa in LTA steps two epoxide first unstable the the catalyzes lipid 5-LOX above, of described formation As the elicit to shown been has RANTES and leukotriene eotaxin LTC of as promote source LTC such and a for stimuli, as bodies required identified several enzymes been and also the bodies have All neutrophils Boyce, 2001). and (Murphy, & eosinophils Bacskai, synthesis of Kanaoka, bodies Borrelli, lipid Jiang, the Furthermore, 2005). (Y. inside al., cells receptors et cysLTs mast Campbell, of human Nielsen, presence and 2007a; the adenocarcinoma to colorectal due of functions nuclei interconnected intracellular/intranuclear spatially cPLA additional are pathway have both CysLTs may the that is of 5-LOX suggested creating components 2008). biosynthetic 5-LOX is (Haeggstr all al., for it that et scaffold and but a (Mandal membrane FLAP nuclear as membranes in act inner binding site also and by Ca can binding 5-LOX outer a process FLAP of in both FLAP-independent activity 5-LOX. inactivated on the to a rapidly complex enhances it is biosynthetic FLAP presenting translocation multiprotein hand, and 5-LOX a other (AA) that the acid cells On arachidonic Serhan, 1992). osteosarcoma to & Evans, in Rouzer, & Dahl´en, shown Lindgren, Vickers, (Samuelsson, been (Kargman, CysLTs LTC and has of FLAP cPLA biosynthesis It where of the envelope 1987). translocation nuclear support the the to to to Upon 5-LOX ready leads and compartmented. membrane 1995) this and Lin, regulated and & highly Hoffmann, increased Smith, is is Regier, & cells calcium in (Mayatepek CysLTs intracellular marker of stimulation, production clinical cell the a that indicate as studies serves LTESeveral thus 1989). and Guhlmann, urine, & and Baumert, 1995). plasma Huber, in (Keppler, accumulates min CysLTs, 4 and 30s (MRP between 4 LTC and (DPEP). 1 enzyme proteins resistance-associated a LTD multidrug where form 2008) via Keppler, cell & the Eisenbeiss, LTC from by exported (GSH) LTA is glutathione to (FLAP) reduced dehydratation to protein A and conjugated 5-lipoxygenase-activating leukotriene (5-HpETE) with epoxyde acid conjunction phospholi- unstable 5-hydroperoxyeicosatetraenoic in membrane–derived the (5-LOX) cell generate 5-lipoxygenase from to by released is metabolized (AA) is A acid phospholipase arachidonic by event, pids inflammatory an During biosynthesis leukotriene cysteinyl Intracellular 2.1. LEUKOTRIENES thus CYSTEINYL could OF triggering inflammation. signaling BIOLOGY in CysLTs cancer-related involvement Targeting block micro- their inflammation. to tumor from strategies the and adapting new tumorigenesis, angiogenesis in offer involvement in influencing of CysLTs their involved by producers to of we migration, are (TME) potent role review and environment and survival, are the this proliferation, In cells into homeostasis, cell pathways. insights Lipid epithelial stromal tissue signaling tumor recent CysLTs cancer. non-cancer and to on and of response inflammation focus cells hallmarks integrated will in cancer an the involves both role of progression that central one tumor CysLTs, Given a as development. recognized play cancer CysLTs now in as is microenvironment such tumor mediators the in Inflammation 5-LOX 2. 1. nye ncsenlluoreebiosynthesis leukotriene cysteinyl in Enzymes m&Fn,21) h oprmnaiaino yLsboytei ugssta hspathway this that suggests biosynthesis CysLTs of compartmentalization The 2011). Funk, & ¨ om 4 hc ntr,i rnfre noLTE into transformed is turn, in which , 4 n LTD and 2 4 4 atclryctslcPLA cytosolic particularly , rdcin(adiaMl,Pofl,&Wle,2001). Weller, & Phoofolo, (Bandeira-Melo, production hog -pT.Tehmn5lpxgns 5LX eeecdstemature the encodes gene (5-LOX) 5-lipoxygenase human The 5-HpETE. through 2+ dpnetmne.I sntcerhwA,rlae ycPLA by released AA, how clear not is It manner. -dependent 4 r ail eaoie ntebodcruaint LTE to circulation blood the in metabolized rapidly are γ- ltmltasetds GT lae h ltmcai oeyto moiety acid glutamic the cleaves (GGT) transpeptidase glutamyl 4 (LTA 4 4 ytae(LTC synthase 2 ycevg ftegyiemit hog dipeptidase through moiety glycine the of cleavage by 2 α 4 hog h eunillpxgnto fA to AA of lipoxygenation sequential the through ) cPLA (c 2 α 4 n -O r ndrc otc ihnthe within contact direct in are 5-LOX and ytei r rsn ihnesnpi lipid eosinophil within present are synthesis 2 α .Oc oiie notectsl AA cytosol, the into mobilized Once ). 4 )t omLTC form to S) 4 Fgr B.LTA 1B). (Figure 4 h otsal mn all among stable most the , 4 4 r meddi the in embedded are S usqetyLTC Subsequently . 1/4 Ru,Hummel- (Rius, ) 4 ihahalf-life a with 2 2 α, α 4 (Schievella, ece its reaches sfurther is 4 Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. T4 aaye h rtcmitdse nteboytei fCsT hog ojgto fGHto GSH of conjugation through CysLTs of biosynthesis the in step committed first the catalyzes LTC4S LTC4S 1999) Sampson, 2.2.3. & Holgate, (Figure (Cowburn, 1994) eosinophils al., human 2003). et Bigby, in (Pouliot TNF- IL-5 proteins by by two upregulated these in and is FLAP of ER FLAP upregulates regulation peripheral GM-CSF addition, coordinated and 5-LOX, 1C).In a membranes to and Similarly nuclear suggesting resting 2002). outer of neutrophils, Soberman, and envelope human & nuclear inner and Brown, the the site McKee, to between Weber, binding localized distributed (Christmas, GSH been a is has a lacks and It FLAP is neutrophils family However, 2002). FLAP identity. activated Austen, MAPEG sequence 2018). & or 33% Colquhoun, (Lam metabolism shares & activity GSH it Costa, GSH-conjugating and whom da eicosanoid with Felipe LTC4S in (Gomes, with involved 5-LOX along protein to membrane-associated acting However, by AA the activity. biosynthesis presents of CysLTs enzymatic thus that member any and carrier activity present 5-LOX substrate not for a necessary does as is FLAP FLAP pathway, that leukotriene demonstrated have the studies in of enzymes other occurrence Unlike the and synthesis CysLTs FLAP 2.2.2. gender-specific between paradoxically link which possible - cancers. females a hormone-dependent from establish cells males (Haeggstr these to from activation to investigation ERK monocytes compared androgen-induced and as to leukotrienes, oxide neutrophils due Intriguingly, produce nitric is to by 2005). capacity inhibited Brock, lower is G. a enhances activity have (Thomas 5-LOX B ERK Werz, peroxidase addition, 2004; (R˚admark, R˚admark, and glutathione In inhibits al., Werz, & kinase and 2002). et directly MK2 Steinhilber, (Luo PKA Src of Szellas, translocation by by Werz, nuclear activation 5-LOX phosphorylation 2002; Tyr94 with by whereas interferes and translocation and 5-LOX Tyr53 synthesis nuclear shown of leukotriene Tyr42, inducing been Phosphorylation by and has formation 2015). (PKA), it leukotriene Samuelsson, A as 2001). kinases kinase & al., different protein Steinhilber, et of by (Spanbroek action Ser523 other cells the the ERK, dendritic through least On maturing modulated and at 1994). and be 1995), McColl, - monocytes potentially al., & in can et Borgeat, activity expression (Murakami 5-LOX Khamzina, 5-LOX cells McDonald, reduces mast (Pouliot, IL-4 mouse neutrophils hand, lack in mature the TGF- IL-3 to in as 1993), due GM-CSF such probably Samuelsson, R˚admark, - factors & (Steinhilber, days growth increased processes. cells 7 is and differentiation expression for cytokines during 5-LOX culture 2007). different increased in Samuelsson, by is kept & (R˚admark, and factors Steinhilber, when Werz, growth 1C) expression required 5-LOX (Figure in lose regulated monocytes tightly be human is can Hence, 5-LOX 5-LOX of associated nuclear is expression LTC cytosol and The from synthesize cytoplasmic 5-LOX to of capacity both import reduced nuclear membrane that eosinophils a nuclear indicate in with the although observations protein & leukotrienes, to MAPK-activated These Mosley, produce translocated p38 to Ferguson, 2017). is activated and (Evans, 5-LOX Pidgeon, calcium synthesis activation, & intracellular LT and increased (Moore phosphorylation for upon (MK2)-mediated prerequisite types, 2 nuclear cell a the kinase all is to In manner, FLAP resting calcium-dependent stimulation 2008). of of a with Hutchinson, fraction upon been compartments in nucleosolic colocalization nucleus nuclear translocation, has and 5-LOX where to cytosolic and 5-LOX to the envelope cytosolic translocated leads in While activation the be detected cellular individual. both Although to cells, 2020). in the resting supposed Singh, detected of Kumar is (Rakesh been gender and neutrophils has male cells 5-LOX the 5-LOX of resting neutrophils, on localization of female depending and in cytoplasm vary distribution of For the nucleus The nucleus. also in the 2005). the may in localized Brock, of resides neutrophils G. region but euchromatin (Thomas human eosinophils, the cells and in (Haeggstr or mast neutrophils cytosol and blood lymphocytes the macrophages peripheral B alveolar either in cytoplasmic in and is residing cells 5-LOX specific, example, dendritic cell-type is as cells well resting as cells, mast nvitro in α n iooyacaie(P)i H- ua ooyi el(ed,Sro oui,& Hodulik, Serio, cells(Reddy, monocytic human THP-1 in (LPS) lipopolysaccharide and ht5LXi hshrltda eea ie nldn:Sr7 yM2 e63by Ser663 MK2, by Ser271 including: sites several at phosphorylated is 5-LOX that – 4 T .Bok nesn re,Ptr-odn pr,1999) Sporn, & Peters-Golden, Fries, Anderson, Brock, G. (T. 3 m&Fn,21) oee,sc tde edfurther need studies such However, 2011). Funk, & ¨ om β n iai 3i L6 el n ooMc6 Mac Mono and cells HL-60 in D3 vitamin and m 08.Telcto f5LXin 5-LOX of location The 2018). ¨ om, ret tal., et urkert, ¨ . Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. r xrse ydffrn eltpso oaie ieetyo oaie el,wihmyrsl nunique in result may which cells, DPEP2) 2015). polarized (DPEP1, al., on Dipeptidases et differently GGT5 2.2.6. (Hanigan and localized GGT5 GGT1 or and tissues, types GGT1 human activity for cell many IFN roles different catalytic In by by 1C). only GGT5 expressed (Figure IL-1 and the by 2015) are up-regulated 2016), Wirsig-Wiechmann, and is & al., GGT1 Wakeham, glycoproteins, et Wickham, 2011). membrane al., (Lukic et II cells (Wickham type cancer family GGT later LTC enzymes, the enzyme, metabolize of extracellular human also members both a could LTC of are that for discovery GGT1 activity GGT5 the human gamma- catalytic to 1991 this less cleave homology in could with 39.5% reported that enzyme with colleagues only GGT5, and the named be Heisterkamp to until thought was bond GGT1 glutamyl years, many For membrane. plasma principal the is GGT1 placenta, brain, in 2.2.5. as well as 1997). cortex, al., adrenal et catalyze for LTC and to of responsible muscle, able production is enzyme skeletal the MGST3 principal heart, tissues. kidney the human and in is liver, found potentially it being where expressed microsomes liver and LTC 1997; Ford-Hutchinson, cells & endothelial Jakobsson, (Scoggan, human testis Ford- LTC and & endothelium with the identity Riendeau, Sj in 44% as Mancini, such LTA a Jakobsson, cells of demonstrates conjugation nonhematopoietic 1996; catalyze MGST2 Ford-Hutchinson, sequence to shown & 1997). to been Mancini, Hutchinson, have according MGST3 (Jakobsson, and (mPGES) MGST2 glutathione family, synthase with this Ford-Hutchinson, Among E Mancini, 1999). Morgenstern, Persson, prostaglandin (Jakobsson, & activities microsomal enzymatic and and properties, structural identity, MGST3, MGST2, MGST1, LTC above mentioned As Mao, LTC & with Luo, Lam, Luo, enzymes (Hsieh, (Serio, Other cells p65 2.2.4. and mast p50 TNF- blood-derived of activation hand, cord involving other mechanism human the transcriptional in 2007). a On via IL-4 1C). cells (Figure and THP-1 2001) 1996) in Boyce, al., of & et Austen, Induction Penrose, (Boyce 2002). eosinophils al., LTC human et LTC that in (Christmas of indicating export Upregulation lumen its 2011). the the LTC for and from membrane in FLAP excluded the localized as C/EBP is of such is side but MAPEGs LTC4S cytoplasmic reticulum encoding of genes the endoplasmic site to peripheral machinery active returned and interconnected The be membrane an membrane. nuclear form nuclear outer they inner the 5-LOX, in LTC with present and together is (Haeggstr that FLAP biosynthesis and that CysLTs membrane for indicating necessary the presented within been trimers has and evidence biophysical they Some when CysLT of biosynthesis transcellular implement to 1.3. cells LTA these LTA allows with the but interact produce cells LTC cannot endothelial therefore and and 2007). cells - Henderson, 5-LOX lack & that (Peters-Golden cells monocytes/macrophages and cells LTA LTA ¨ ostr (a&Ase,2002). Austen, 4(Lam& 4 4 niecnetoa S-rnfrss LTC GSH-transferases, conventional Unlike . m aoso,Hibre,Plba,&Haeggstr & Palmblad, Heimburger, Jakobsson, ¨ om, γ- rdcin(cga ta. 97.MS3peet 7 mn cdiett ihLCSadi widely is and LTC4S with identity acid amino 27% presents MGST3 1997). al., et (Scoggan production α, ltmltasetdss(G1 GGT5) (GGT1, transpeptidases Glutamyl C/EBP δ, 4 pouigcls(ar ta. 05.Ti oi ilb ute icse nparagraph in discussed further be will topic This 2015). al., et (Capra cells -producing n C/EBP and 4 γ- rmLTA from LTC ltmltasetds htcevsguai cdfo LTC from acid glutamic cleaves that transpeptidase glutamyl 4 samme fteMPGspraiy hsfml ute opie FLAP, comprises further family This superfamily. MAPEG the of member a is S 4 4 smdae yTGF by mediated is S sepesdi el fmeodoii uha aohl,esnpis mast eosinophils, basophils, as such origin myeloid of cells in expressed is S 4 ε, activity S 4 NF- n S htmyocrudrptohsooia iutos(Jakobsson situations pathophysiological under occur may that GSH and 4 hnGT Wchm et ok aia,21) G1and GGT1 2011). Hanigan, & Cook, West, (Wickham, GGT1 than κ n al rwhrsos rti ER1 Hgis&Hayes, & (Higgins (EGR-1) 1 protein response growth Early and B m&Fn,21) LTC 2011). Funk, & ¨ om 4 smdae yasre ftasrpinfcossc as such factors transcription of series a by mediated is S nvitro in 4 β 4 γ osntcnuaexnboisadi eetv for selective is and xenobiotics conjugate not does S nTP1cls(idc ta. 99,I- n IL-5 and IL-3 1999), al., et (Riddick cells THP-1 in n L4i ua arpae Hngn Gillies, (Hanigan, macrophages human in IL-4 and m 01.MS2i rdmnnl eetdin detected predominantly is MGST2 2001). ¨ om, ohterdcino -PT o5HT and 5-HETE to 5-HPETE of reduction the both 4 usrt uha ltlt,vsua smooth vascular platelets, as such - substrate 4 4 sa 8kammrn rti that protein membrane 18-kDa an is S n consfrLTC for accounts and S α oneuae LTC downregulates 4 sas eetdi several in detected also is S 4 omfntoa dimers functional form S β nA4 pteillung epithelial A549 in 4 ofr LTD form to 4 oLTD to 4 4 expression S ytei in synthesis 4 although 4 4 tthe at must 4 Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. iyt yLsi h olwn re LTD LTC : to order following equally CysLT the While in 1). CysLTs (Table CysLTs to toward nity affinity differential show receptors These uloie nms el Mlo ta. 03 lhuhi a ae eosrtdta LTD that demonstrated 2005). later al., was et it (Capra although monocytes in 2003) receptors al., separate et through (Mellor signal cells diphosphate CysLT mast both in and nucleotides receptors, nucleotide LTE P2Y to for affinity substantial exhibits introduced later was nomenclature CysLT the This of 1992). characteristics pharmacological al., et CysLT (Labat that CysLT the observation antagonists CysLTRs the Henderson, of on & class based (Peters-Golden LTC cytoplasm, a either the cAMP to by in resistant in induced proteins reduction contractions G trachea and with CysLT pig interact of calcium and CysLT classification intracellular cells The (GPCRs): in inflammatory 2007). receptors of increases membrane eliciting protein-coupled plasma thereby G outer the of on sets cated two through CysLT signal tumor leukotrienes the Cysteinyl adapting in cancer growth. involved and tumor RECEPTORS potentially direct cells, LEUKOTRIENE or conditions endothelial CYSTEINYL immunosuppression inflammatory platelets, added inflammation, cells, were under angiogenesis, immune platelets influencing other by that washed each microenvironment known when with well LTA hand, interact is other the cells it the of of because On 50% instead underestimated it. environment than largely synthesized extracellular more that LTC the that cells PMNL, into to the shown patho- released by been in was metabolized CysLTs has (PMNL) of being It leukocytes production cancer. the polymorphonuclear as to bovine contributor such important situations an physiologic trafficking represent transcellular could facilitate metabolism can Transcellular and and chaperones liposomes as Albumin, act 1989). water. to Serhan, by shown attack hydrolytic been LTA from have shielded of protein be binding to demonstrated acid has later that fatty was molecule process observed unstable transcellular vascular highly This well or a 2015). platelets, been al., cells, et has endothelial (Capra with vivo biosynthesis,” LTC4S incubated express “transcellular are which 5-LOX cells, as expressing smooth defined LTA monocytes or transformation then phenomenon which neutrophils and inflammation, in This when of types type cell sites cell multiple and CysLTs. one of tissues into cooperation in tumor the in occurs through particular AA manner in their complex of tissue, more enzymes for a a the LTA in within required contain CysLTs place unstable to takes of enzymes the found production the were of the 5-LOX conversion that all of clear biochemical express expression the lacking that for cells leukocytes responsible many However, stimulated 1A). by (Figure produced synthesis et primarily (Eisenach are CRC CysLTs and (IEN) Neoplasia (CRC) biosynthesis Intraepithelial several CysLT cancer High-Grade Transcellular colorectal in of in aberrantly marker increased expressed a is is as 2013). expression al., identified that DPEP1 been metalloproteinase controversial. has remains zinc-dependent and role a its is although DPEP1 cancers LTD wide 2003). from a Lieberman, hydrolyzes LTD glycine which of cleave dipeptidase conversion to membrane-bound the able 55kDa including a substrates, is of dipeptidase) range renal as known (also DPEP1 namuemdlo eioeliflmain(aii i´n asm,Mrh,&Sl,20) LTA 2009). Sala, & Murphy, Gij´on, Ransome, (Zarini, inflammation peritoneal of model mouse a in 2 4 o LTC for R uigcl ocl neatos(ikno imr ole,Brlh,&Mrh,20;Foe& Fiore 2004; Murphy, & Bernlohr, Voelker, Zimmer, (Dickinson interactions cell to cell during 2 eetrwsnt ae,tecoigo hs eetr n19 n 00lreycnre these confirmed largely 2000 and 1999 in receptors these of cloning the Later, not. was receptor 4 4 a h anmtblt xrtd(aa et,&Flo 96.Ti hnmnncudbe could phenomenon This 1996). Folco, & Testa, (Sala, excreted metabolite main the was n LTD and 4 n LTD and 4 ihalwant LTD : affinity low a with 4 n CysLT and , 4 1 ofr LTE form to n CysLT and R (aak,Meaa utn 2013) Austen, & Maekawa, 4(Kanaoka, 1 eetrwssniiet niiinb lsi naoit,whereas antagonists, classic by inhibition to sensitive was receptor 4 > 3 4 1 ,as nw sGR9 o LTE for GPR99, as known also R, 1 LTC n CysLT and spse nt eodcl ocmlt h transformation the complete to cell second a to on passed is n CysLT and R 4 4 2 ni h dnicto fDE2(ai,Si uvs & Cuevas, Shi, (Habib, DPEP2 of identification the until rLTD or a ntal ae ntedffrnilpolso guinea of profiles differential the on based initially was R 4 >> 4 5 4 oLTE to LTC = LTE 4 2 n hte h epnewsbigsniieor sensitive being was response the whether and eetr Hiee l,20;Lnhe l,1999). al., et Lynch 2000; al., et (Heise receptors 4 2 Lnhe l,19) CysLT 1999), al., et (Lynch aebe eotdt inli epneto response in signal to reported been have R 4 4 twsln eivdt eteol enzyme only the be to believed long was It . >> 4 notefia iatv yLs ti now is It CysLTs. bioactive final the into LTE yLR r hlgntclyrelated phylogenetically are CysLTRs . 4 Hiee l,20) CysLT 2000). al., et (Heise 1 4 eetrhsaseicaffi- specific a has receptor hs eetr r lo- are receptors These . 2 eetrresponds receptor 4 4 rdcdby produced n uridine and 3 nvitro in 1 only R and R 4 is H in Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. n K51 r loatv nCysLT on active also are MK-571, 2). and (Table Zafirlukast CysLT and both Pranlukast, CysLT expressing Montelukast, to cells as in such functions drugs physiological antiasthmatic al., Some 2005). by et targeted al., Campbell, is et receptor (Nielsen, (Capra This Gq mechanism through C-dependent commonly kinase most protein type, a cell on the on LTD depending CysLT2005). Gi-protein the the of and Activation Gq- calcium. blood intracellular (B of cytokines peripheral and elevation as factors mediators transcription inflammatory such of of types activation release activation, and cell leukocyte permeability, several vascular in increased (B bronchoconstriction, as cells muscle well smooth as and CysLT cells, 1999). heart, hematopoietic and lineage myeloid placenta, other intestine, leukocytes small spleen, lung, CysLT CysLT CysLT of CysLT regulation (B contraction, activation cell muscle leukocyte smooth and permeability, of vascular modulation cysteinyl-leukotriene-induced mediate both they ob novdi yLssgaig hs diinlrcposicueGR7(in ta. 06,P2Y 2006), al., et (Ciana GPR17 include receptors additional These signaling. CysLTs PPAR in involved be CysLTto the to allergic addition In in role a receptors CysLTs-related suggesting inflammation. identified and 2013) 2 Other 2018) type al., al., with et et associated (Kanaoka (Bankova disease responses functions respiratory inflammatory cellular and modified during having leakage (Table cells vascular CysLT 2004) brush caused of Encinas, airway role & IL-25-producing Tanabe, pathophysiological Miyawaki, of the Watanabe, number about (Inbe, known kidneys is and Little tract 1). respiratory the of LTE tissue the to affinity high with P2Y or GPR99 Recently, CysLT inhibit reportedly CysLT CysLT 15b of eosinophilic compound inhibitor airway and selective platelet-mediated 2). BayCysLT2, no enhances (Table currently HAMI3379, and specificity is 2018) but There al., practice, 2019). et clinical al., (Liu et cells (Liu epithelial Friend, CysLT inflammation Maekawa, alveolar 2004). (Beller, al., from fibrosis et IL-33 tissue Hui of and 2004; permeability, Kanaoka, vascular & inflammation, Austen, to CysLT contributes using rather Studies but 1). (Table CysLT platelets overexpressing and mice cells, or muscle smooth vascular cells, endothelial (B ges/monocytes CysLT otlks.GR7hsas ensont omadmrwt CysLT with dimer kidney) a and form heart, to (brain, CysLT shown LTC injury of been including CysLTs, activation ischemic also endogenous undergo has by activated GPR17 typically is GPR17 can Montelukast. that 2006). al., organs et in (Ciana expressed highly receptor LTE to binding LTD preferential to affinity substantial shown have γ 1 1 2 2 3 2 noe 3-mn cdpoenadi xrse nmn ua ise Tbe1 including 1) (Table tissues human many in expressed is and protein acid 337-amino a encodes R R noe 4-mn cdpoenwt 0 euneiett oCysLT to identity sequence 40% with protein acid 345-amino a encodes R R R macropha- and cells, mast basophils, eosinophils, including leukocytes, in expressed mainly is R SiaaPrcuie l,20) n P2Y and 2008), al., et Paruchuri (Sailaja 1 ae natgns ffcs oee,ms ektin eetratgnss xetMontelukast except antagonists, receptor leukotriene most However, effects. antagonist on based R 4 iiitddsniiaino CysLT of desensitization -initiated 1 sgnrlyascae ihtecasclpyilgclfntoseiie yCsT,sc as such CysLTs, by elicited functions physiological classical the with associated generally is R c ta. 01 eesGle edro,20) u loi iwymsl el,vascular cells, muscle airway in also but 2007), Henderson, & Peters-Golden 2011; al., et ¨ ack 1 Meaa aetir,Ase,&Knoa 09.Hwvr t oea CysLTR a as role its However, 2009). Kanaoka, & Austen, Balestrieri, (Maekawa, R 15 1 (aak ta. 2013) al., et 4(Kanaoka CysLT , rvosydsrbda nooltrt receptor oxoglutarate an as described previously , (..Snh ut,Dsia,&Ry 2010) Ray, & Dastidar, Gupta, Singh, 4(R.K. 2 ntelnsidct htCysLT that indicate lungs the in R 2 n CysLT and , 4 2 hra h atrtorcpos PPAR receptors, two latter the whereas , .I at CysLT fact, In R. Tbe2.CysLT 2). (Table 3 1 sascae ihisitraiainwihi dependent is which internalization its with associated is R eetr,adtoa eetr aercnl enreported been recently have receptors additional receptors, c ta. 2014). al., et ¨ ack 2SiaaPrcuie l,2009) al., et Paruchuri 12(Sailaja 2 a ensont eit h ytei n release and synthesis the mediate to shown been has R 6 c ta. 04.CysLT 2014). al., et ¨ ack 1 1 1 n CysLT and R rgessgaigtruhete rbt the both or either through signaling triggers R n CysLT and R 3 .SgaigtruhCysLT through Signaling R. 3 P1 sada rclnucleotide-CysLTs uracil dual a is GPR17 . RAepeso smil eetdin detected mainly is expression mRNA R 2 osntmdaebronchoconstriction, mediate not does R 1 hspeetn LTD preventing thus R 2 2 xii eudn ciiisas activities redundant exhibit R eetr aebe attributed been have receptors R , a enietfida CysLT as identified been has P1 n P2Y and GPR17 . 1 4 skont inlthrough signal to known is R c ta. 04 yc tal., et Lynch 2014; al., et ¨ ack n LTD and γ, 2 n P2Y and 1 hthsetrdinto entered has that R .(es ta. 2000). al., et (Heise R. 4 n niie by inhibited and , 2 3 -ecetmice R-deficient 12 nrae the increased R 2 aesona shown have ihhigh with R 6 4 -mediated receptors 3 R 6 , Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. rgoi nptet ihpott,bes,adclncnes(B CysLT cancers in colon mutation CysLT and hotspot of a breast, identified expression prostate, studies strong Some with Furthermore, patients Clinically, 2011). Ehrnstr in CysLTRs. al., (Magnusson, prognosis of et cancer Venerito expression testicular 2010; the and Yoshimura, and cancer survival colon patient cer, between (B relationship cancers various a CysLT in suggest CysLTRs for studies role Many a indicate also CysLT studies several whereas However, diseases diseases. inflammatory immune chronic and and acute vascular CysLT many of of pathogenesis role the The in implicated been have receptors leukotrienes CysLTs human cysteinyl in of expression functions These Bax Pathophysiological increase 1998). 3.2. to Myers, and & pancreatic Mcl-1, (Ghosh 2002). in and cells al., apoptosis protein et cancer induce (Tong Bcl-2 prostate to cells decrease and shown cancer to 2002), been pancreatic shown Adrian, has later & inhibition were 5-LOX Witt, inhibitors Ding, studies apoptosis. Several (Tong, in cells elucidated. 5-LOX fully Douglas-Jones, cancer for been Jiang, not role have G. a tumorigenesis (W. to suggest contributes prognosis 5-LOX which poor by a a mechanisms The com- is with cancers correlates FLAP breast in expression before, of expressed 2006). this mentioned aberrantly stages Mansel, and also As colorectal early & is tissues mRNA in in normal FLAP 2007). metastasis 5-LOX to 5-LOX. Barresi, of node pared of activity & lymph the role Tuccari, for and the necessary Vitarelli, stage protein neoplastic support colorec- Grosso, tumor early results to with (Barresi, These the transformation correlates adenocarcinomas malignant 2014). during 5-LOX 2010). Bentrem, for Furthermore, present & al., factors be Grippo, carcinogenesis. et risk (Knab, to (Wasilewicz high cancer disease shown adenocarcinoma invasive with breast tal to been and correlates progression prostate positively has before overexpression pancreatic, expression well in 5-LOX renal, 5-LOX cancer, expressed lung, expression pancreatic constitutively of 5-LOX oesophagus, 2017). and changes that colon, stimuli Pidgeon, including indicate pro-inflammatory & types reports by most (Moore cancer Although upregulated few of but a 2010). types pathway, number Dubois, epithelia cancer cyclooxygenase a & normal several (Wang the in tumorigenesis in on absent increased found is focused with gen- is associated been 5-LOX is be 5-LOX of has to and attention metabolism shown carcinogenesis Altered been in has pro-carcinogenic. involved and being are as pathways considered lipoxygenase erally that indicates evidence pathway Emerging 5-LOX of metabolism Altered 3.1. CANCER IN LEUKOTRIENES CYSTEINYL 3. LTE LTE whether of unclear CysLT effect still with is an interacts it cells, signaling However, CHO 2010). transfected al., in et Erk P2Y of that activation shown aggregation induce platelet later prevent P2Y was to used It 2015). clinically (Cattaneo, is Clopidogrel thrombosis antagonist CysLTand selective the for P2Y with receptor inhibition 2011). receptor CysLT supporting Ko, receptors. a CysLT P2Y & as of the Au, activation inhibit acts the to that mediates shown survival but been CysLTs cell with of directly promoter bind P2Y a 2010). as Rosenkilde, identified & (Benned-Jensen disputed been has 1 soeepesdi ati acr ea elcrioa rniinlcl acnm,pott can- prostate carcinoma, cell transitional carcinoma, cell renal cancer, gastric in overexpressed is R 1 sntol eldsrbdi eprtr iesssc satm,btas nchronic in also but asthma, as such diseases respiratory in described well only not is R 12 sacnnctp fprnri eetrta satvtdb D.TeP2Y The ADP. by activated is that receptor purinergic of type canonic a is , 12 3 6 -eitdactivation. R-mediated eetri eurdfrLTE for required is receptor eetr(.Jag orli asa,Knoa oc,20;Lu Chow, Lau, 2009; Boyce, & Kanaoka, Bacskai, Borrelli, Jiang, (Y. receptor 12 eetrwsiiilyidentified initially was receptor 2 a enpriual novdi adoaclrdiseases. cardiovascular in involved particularly been has R 2 7 4 sadie noeei va eaoaadi blue in and melanoma uveal in oncogene driver a as R id ietyt P2Y to directly binds 6, m le,&Sj & Olsen, ¨ om, 4 mdae umnr namto n can and inflammation pulmonary -mediated uiegcsbaiyo eetr,hsbeen has receptors, of subfamily purinergic a c ta. 04 ag&Dbi,2010). Dubois, & Wang 2014; al., et ¨ ack 4 niie yCoiorl(.K Singh K. (R. Clopidogrel by inhibited nsilico in 12 lne,20;Mtuaa& Matsuyama 2007; ¨ olander, c ta. 2014). al., et ¨ ack n hte t downstream its whether and 1 1 sarcpo o LTE for receptor a as naoit aealso have antagonists R orltswt poor with correlates R 1 .P2Y R. 6 osnot does 12 4 . Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. rti xrsini ooyi ekmaclsvaaPKC a via cells leukemia monocytic in expression (Wikstr protein cells LTD Caco-2 and that colon Int407 suggest and LTD in Sj pathways. 2003) & signaling prostaglandins al., Azemovic, MAPK/Erk1-2 the et Nielsen, by and Massoumi, (Ohd CysLTs Ramin cells between and 2015; intestinal crosstalk activation al., a in 3 et production (Bellamkonda caspase (PGE2) cells or E2 cancer prostaglandin 8 and caspase Wikstr expression LTD with COX-2 2003; 2003). interfering al., et by al., (Ohd cells et signaling intestinal MEK/Erk in activating inhibition by COX-2 by induced eldahidcdb oso arxcnat yokltlitgiyo xrclua ioei atr and factors counteracting mitogenic by extracellular apoptosis or integrity against cytoskeletal cells contact, protecting matrix in of role loss a by plays LTD induced potentially death MAPK cell 1998). Shimizu, & HT-116 and Caco-2 cancer colon in and 2003), al., et Sj Ohd & 2006; Sime, al., (Bellamkonda, et cells Mezhybovska 2006). (Maryna al., cells et Int407 Mezhybovska (Maryna survival LTD promote Hence, to Bcl-2 with interact physically to induces only not GSK-3 the reduces and & Larsson, of Juhas, location Hallberg, Paruchuri, Wikstr (Sailaja pathway of Ras-dependent activation PKC by parallel Ras-independent, LTD a a 3). cells, (Table via via muscle Sj pathways cells and multiple smooth Int407 through ERK-1/2, intestinal cells, survival of non-tumoral and marrow in proliferation bone proliferation cell including cell promote (B types to cells shown cell intestinal been various and in cells, proliferation endothelial cell induce microenvironment CysLTs tumor survival a and to Proliferation apoptosis pro-inflammatory microenvironment 3.3.1. proliferation, factors, normal growth cell a such secrete regulate to switch 2), turn cells that Figure in immune factors which and 3, (TME). epithelial angiogenic cells, (Table of and cancer mechanisms induction on mediators several the receptors or These through CysLTs migration, types. progression of and cell activation cancer tumor and the modulate normal as various can by lipids produced are bioactive CysLTs pro-inflammatory carcinogenesis aforementioned, in As leukotrienes cysteinyl of is Role receptors 3.3. two these between outcome. balance disease the and that progression suggest tumor thus data for These important tumorigenesis. promote may CysLT which of CysLT expression of Lack high already CysLT CysLT the upregulates Sj regulates to but & Juhas, cells due Bengtsson, cancer possibly Parhamifar, colon only, LTD and cells Interestingly, cells transformed 2007). intestinal al., et non-transformed (Magnusson both CysLT inhibition of growth CysLT expression and and reduced prognosis cells whereas poor development, with tumor associated in is receptor this for role CysLT portant types cancer other CysLT in although nevi lne,20) LTD 2002). ¨ olander, 4 rmtsitsia el uvvlb asn K-eedn peuaino active of upregulation PKC-dependent a causing by survival cells intestinal promotes 1 ¨ om, a ensont inlsria n rlfrto nclncne Tbe3,sgetn nim- an suggesting 3), (Table cancer colon in proliferation and survival signal to shown been has R β- h,&Sj & Ohd, ¨ 4 aei n usqetMCadCN1tasrpini T1 el,btnti T9cells, HT29 in not but cells, HT116 in transcription CCND1 and MYC subsequent and catenin rmtscl uvvlb nraigepeso fteat-ppoi rti c- nintestinal in Bcl-2 protein anti-apoptotic the of expression increasing by survival cell promotes 2 a aiiaetefraino CysLT of formation the facilitate may R β- 1 inligi ua atcls(.Jag orli aak,Bcki oc,2007b). Boyce, & Bacskai, Kanaoka, Borrelli, Jiang, (Y. cells mast human in signalling R β- aei inln i IKdpnetpopoyaino GSK3 of phosphorylation PI3K-dependent a via signaling catenin 4 4 aei rnlcto otencesbtas otemtcodi hr ti suggested is it where mitochondria the to also but nucleus the to translocation catenin inl wthfo eldaht elsria.LTD survival. cell to death cell from switch a signals u o LTC not but - lne,20) nclncne el,LTD cells, cancer colon In 2006). ¨ olander, 4 idcdatvto fCysLT of activation -induced β- nue erdto of degradation induced lne,21;Wikstr 2015; ¨ olander, lne,20) thsas endmntae htCysLT that demonstrated been also has It 2008). ¨ olander, 4 a nedbe hw oices elsria yup-regulating by survival cell increase to shown been indeed has - c ta. 04.Teatvto fLTD of activation The 2014). al., et ¨ ack 2 2 inln ed otria ieetaino oo carcinoma colon of differentiation terminal to leads signaling R em oeetat-acrpoete Sae ta. 2018). al., et (Slater properties anti-cancer exert to seems R β- aei Slm adDje,&Sj & Sand-Dejmek, (Salim, catenin 1 lopooe netnlcl rlfrto n survival and proliferation cell intestinal promotes also R 8 ¨ om, 1 ooies edn oicesdLD signaling, LTD4 increased to leading homodimers, R h,e l,20) LTD 2003). al., et Ohd, ¨ α m ua,&Sj & Juhas, ¨ om, n a1sgaigptwy(ohn,Izumi, (Hoshino, pathway signaling Raf1 and ¨ om, 4 -CysLT 4 h,e l,20) oerslsfurther results Some 2003). al., et Ohd, idcdices fCX2i mediated is COX-2 of increase -induced ¨ 4 1 inln nue ula trans- nuclear induces signaling R sal ourglt CysLT upregulate to able is 4 lne,20;Wikstr 2003; ¨ olander, skont nraeMAPK increase to known is 1 ncne el (Yudina, cells cancer in R 4 lne,20) suggesting 2003), ¨ olander, 4 CysLT - β lopeet apoptosis prevents also Mrn Mezhybovska, (Maryna ε- 1 lne,21) LTD 2014). ¨ olander, xrsini non- in expression R eedn activation dependent 2 nclncancer colon in R 1 β inln has signaling R -nern and 1-integrins 2 negatively R ¨ om, 4 induces 2 Ohd, ¨ in R 4 Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. ae h deiepoete n irto fCc- el yu-euaigCX2adsiuaigPGE2 stimulating and COX-2 LTD up-regulating I. of by collagen expression cells to and Caco-2 activation adhesion of enhanced increasing in migration by resulting cells and production in cancer properties role colon adhesive important of LTD the an migration 2014). lates plays al., and which et adhesion GTPase (Magi cell-matrix small expression. of a Tiam1 activation, increasing Rac1 by of migration, wave cell second EGF-induced the gulated rgntrcls(Ps nue yctknssc sI-,adatvtsteMP/r aha leading pathway MAPK/Erk the activates and IL-3, as such cytokines increase by to induced (HPCs) cancer cells regulate progenitor to capacity this potential their whether LTD indicating However, leukotrienes homeostasis that cell recognized. suggest stem growth. studies well of cell Some is regulation stem unclear. the progression remains in tumor (CICs) involved in cells are cancer-initiating mediators of lipid promotion inflammatory includes of role 2018). Sjolander, The & markers Satapathy differentiation 2017; cells cell al., Cancer-initiating et induce (Mehdawi to 3.3.3. cells and cancer 2007), colon al., in MMP-9 et and (Magnusson CysLT of MMP-2 cells Conversely induction decrease the cancer and 2017). in breast involved al., mediator MCF-7 be et in to key (Vinnakota known migration a LTD cancers metallopeptidase a expression, breast 2014). MMP-9, in E-cadherin of al., EMT decreases expression LTD increases et and and (Salim metastasis. cells cells, and cancer process cancer invasion EMT colon cell the HT-116 cancer of of to step migration essential the an increases is (EMT) transition Epithelial-mesenchymal & Dib, Broom, Paruchuri, (Sailaja LTD cascade PI3K-Rac metastasis. the and of invasion activation tumor the for Sj through step migration essential cell an testinal is migration Cell Invasion 2018). Migration, Sjolander, & 3.3.2. Satapathy 2017; LTC al., However, et 2011). (Mehdawi mucin-2 al., et and et Mehdawi sucrase-isomaltase Bengtsson, 2007; (Magnusson, al., cells TNF et cancer (Magnusson breast CysLT lines MCF-7 CysLT 2018). in cell Sjolander, apoptosis carcinoma & of colon Satapathy in CysLT 2017; CysLT While inhibition cells, al., cancer subtype. growth colon receptor and and the cells epithelial differentiation on intestinal depend in survival also and CysLTs proliferation of effects proliferative The CysLTs of production endogenous impairs Sj that CysLT inhibitor nuclear 5-LOX that CysLT cell-permeable suggesting by surface induced cell inhibits be and nuclear could but exhibit response cells CysLT cells cancer surface cancer colon cell Colon and of cells. blockade lines intestinal cell non-tumoral intestinal Sj in non-tumoral only & survival both of Paruchuri proliferation Sailaja PKC reduces significantly 1998; a al., cells: activities LTD Int407 et 1/2/p90 versatile that in (Hoshino the shown pathways conditions explain been signaling could inflammatory pathways has under signalling It intracellular cells 2003). distinct in two CysLTs least of at of presence The enhancing eeto n rlfrto uigiflmain(ohlre l,20) LTD 2009). al., et LTD Also, (Boehmler inflammation during ALDH proliferation and retention lne,20) neiemlcrioaA3 el,bt LTD both cells, A431 carcinoma epidermal In 2005). ¨ olander, Sj & Juhas, Mezhybovska, Paruchuri, S. 2005; ¨ olander, 4 α + 2 u o LTC not but - inln,dwrgltsCX2epeso,adicessepeso ftedffrnito markers differentiation the of expression increases and expression, COX-2 downregulates signaling, inln peuae uo-upesrezm 5PD nclncne el i N/P1and JNK/AP-1 via cells cancer colon in 15-PGDH enzyme tumor-suppressor upregulates signaling R RSK ouain akro acriiitn el nCC n hi eitnet aito n 5-FU. and radiation to resistance their and CRC, in cells cancer-initiating of marker a population, 4 β α -nerndpnetahso oclae V(.Msom Sj & Massoumi (R. IV collagen to adhesion 1-integrin-dependent rmtdepeso fsl-eea ee nALDH in genes self-renewal of expression promoted aha rmtn rlfrto SiaaPrcui&Sj & Paruchuri (Sailaja proliferation promoting pathway 4 β and 1 4 α 5 rLTE or β nerndpnetahso ugsigta yLsmycnrbt oHPCs to contribute may CysLTs that suggesting adhesion integrin-dependent 1 1 1 mar rlfrto inln,btntcl uvvl oee,a apoptotic an However, survival. cell not but signaling, proliferation impairs R 4 a oei yL uvvlsgaln Nesn asui onrid & Sonnerlind, Massoumi, (Nielsen, signalling survival CysLT in role a has R i CysLT via - 4 a nuecl uvvladpoieainb ciaigtoparallel two activating by proliferation and survival cell induce can α/ 1 RBptwypooigcl uvvladaPKC a and survival cell promoting pathway CREB inln uprspoieaino D4 hematopoeitic CD34+ of proliferation supports signaling R 4 2 ute rmtscl nainadETi W8 colon SW480 in EMT and invasion cell promotes further inln loapast aen ffc ntelevel the on effect no have to appears also signaling R 9 lne,2006). ¨ olander, α 2 4 β + -nern RmnMsom ta. 2003). al., et Massoumi (Ramin 1-integrins n LTC and Is h ooyfraincpct,and capacity, formation colony the CICs, 2 inln a sesdt euecell reduce to assessed was signaling R lne,20) CysLT 2003). ¨ olander, 4 a enivle nteregulation the in involved been has 4 idcdCysLT -induced lne,2001). ¨ olander, 4 nue o-rnfre in- non-transformed induces 4 2 ly oei terminal in role a plays R n PGE and 1 inln induces signaling R 1 inln re- signaling R 2 1 inhibition R nraethe increase 4 ¨ olander, ε/ through 1 4 and R ERK- regu- 4 Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. Rsrs-rgee eldah orltn ihrdcdcevg fcsae3 hra niiino the of inhibition LTC whereas of 3, use caspase The of cleavage ROS. reduced of with generation correlating and death, (NOX4) LTC cell 4 translo- stress-triggered LTC oxidase nuclear ER elicits triggers pathway NADPH this ER-stress of of Activation mutations. cation translocation. increased nuclear CysLTR and and machinery instabilities biosynthetic genomic to ing LTC LTD damage for DNA 2015). role Oxidative al., a et 3.3.4. supporting (Bellamkonda further progression cancer tumor thus colon and of characteristics model stemcell-like xenograft cancer a in growth tumor arpae TM) uha 2mcohgs lya motn oei h rgeso fcne.M2 cancer. Tumor-associated of progression 2008). the al., in et role Schain TNF important 2015; including an com- al., cytokines play pro-inflammatory et various other macrophages, (Han secrete of M2 TME synthesis macrophages as a the such to promote (TAMs), contributing and macrophages cells site a tumor immune TNF play the by and which into pounds IL-6, lymphocytes, eosinophils IL-8, of Th17 as chemotaxis but in LTD to such and regulation 2015). cytokines, 1998) immune Lee, of al., on & et production LTB4 (Kim (Hoshino leukotriene tumorigenesis cells and in THP-1 5-LOX role leukaemia of monocytic LTD role Dubois, human chemoattractants. & in the leukocyte (Wang potent on angiogenesis also induce focused are and CysLTs have phenotypi- inflammation are maintain studies that can Many cells cells immune 2010). immune of normal recruitment the to inflammation, different chronic cally or completely tumor-associated been to inflam- however response which of not In by incidence has mechanism progression the and 2010).The reduce transformation Karin, cell aspirin & resolved. tumor Greten, as to (Grivennikov, contribute such mediators cancer studies (NSAIDs) matory Several prostate In- drugs 2008). and 2010). anti-inflammatory Bonaz, LTE breast, Dubois, & urinary nonsteroidal colon, & Bessard, and that Moreau-Gaudry, (Wang inflammation Pofelski, shown (IBD) of (Stanke-Labesque, sites have disease IBD at bowel for increased inflammatory through biomarker are cancer with CysLTs initiation, a and patients as from inflammation such in tumorigenesis, chronic mediators arises between of promo- flammatory that association of step CRC strong capable every TME in A with a progression. occurs associated to metastatic microenvironment is to eicosanoids tissue promotion, TME normal and tumor This a chemokines from progression. cytokines, shift tumor the as ting to such contribute CysLTs, mediators as pro-inflammatory such inflammation, chronic the During activity, NADPH increasing by Abhyankar, Yudina, cells Mezhybovska, (M. Caco-2 genes cancer DNA LTD mitochondrial colon Sj of 2004). and & transcription al., the cells and et Int407 ratio, (Elstrom ATP/ADP non-transformed cells cancer both in in glycolysis aerobic LTD stimulate of to 2014). induction LTD al., via regulation oncogene. et and c-Myc c-Myc (Salim transformation regulator” the “master of in the by implicated transcription mediated are activates are - and effect Warburg growth, the cell as cancer known of also - glycolysis in Changes energetics cell of Deregulation 3.3.5. LTC of nature intracrine the rnfre,ad5LXadLCSi ohnntasomdadcne ellns TNF- lines. cell cancer and TNF- non-transformed both 2017). in LTC4S al., and et 5-LOX (Vinnakota and cells transformed, cancer colon TNF LTD in in as enriched well as medium cells, macrophage tumor of metastasis and ...Tmrpooiginflammation Tumor-promoting 3.3.6. lne,2009). ¨ olander, 4 4 rnpre MRP transporter a ensont rmt xdtv N aae rmr rvro acngnss contribut- carcinogenesis, of driver primary a damage, DNA oxidative promote to shown been has 1 yrvra osntrdc lae aps- ees hrb ute demonstrating further thereby levels, caspase-3 cleaved reduce not does reversan by 4 nue h IKAtsgaigptwyi n47cls hc a enshown been has which cells, Int407 in pathway signaling PI3K-Akt the induces 4 cino eldah(vs,HrTl aa,Mi,&Rbnti,2015). Rubinstein, & Meir, Barak, Har-Tal, (Dvash, death cell on action α n LTD and 4 4 hc a ute rmt muecl nlrto.M2-like infiltration. cell immune promote further may which i ciaino rncitoa euao G-,induces EGR-1, regulator transcriptional of activation via , 4 β- rmtsMP9epeso n nuto fteEMT the of induction and expression MMP-9 promotes aei ula rnlcto nitsia n47cells Int407 intestinal in translocation nuclear catenin 10 α α α n T4as nraeCX2epeso nnon- in expression COX-2 increase also LTD4 and yHdknlmhm el hc a contribute may which cells lymphoma Hodgkin by hc skont rmt rlfrto,invasion proliferation, promote to known is which 4 a ensont nueaceoatcresponse chemotactic a induce to shown been has 4 lotigr eaoi activity metabolic triggers also 4 ytei yMGST2-based by synthesis 4 naoit attenuates antagonists 4 4 CysLT - ntepooinof promotion the in α n LTD and 4 1 a ev as serve can signaling R 4 oa to , Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. aCsT,ihbt aa irvse ugot rmrttoai otcrns n ohdusihbtan inhibit drugs antagonist both CysLT2R and HUVEC rings, the in aortic not formation thoracic but tube rat Montelukast, disrupts from antagonist outgrowth and LTD CysLT1R microvessel level, basal The protein inhibits 2018). VEGFR-1 BayCysLT2, Sjolander, the decreases & cells, (Satapathy cancer LTC colon through against expression 15-PGDH of LTC restoration between hand, action synergistic potential a LTC 1994). vitro Maragoudakis, in & Pipili-Synetos, (Tsopanoglou, system endothe- membrane induce vascular to and shown mice, 2 consistently WT chain been Wikstr in light have CysLTs myosin implants proliferation Rho-dependent Matrigel 2019). cell sig- the al., and LTD4-CysLT2R lial et via ECs (Duah permeability permeability. murine axis the and vascular isolated (VE)-cadherin contraction is endothelial in with CysLT2 ECs angiogenesis associated enhance particular, regulate to is In to and and shown cells. cells been muscle CysLT has these smooth vascular naling by microenvironment. and expressed the (ECs) CysLTR CysLT in cells main between cells endothelial interactions non-cancer vascular of in and possibility detected cells the leukotrienes cancer suggesting produce by receptors to CysLT produced general, capacity express inner-tumor In the they on however formation. have pro-angiogenic dependent tubule expression; various not and heavily secrete do migration TME are proliferation, cells the invasion recruitment, in endothelial cell and cells endothelial growth Several stimulate stability. tumor that vascular factors as by influenced cancer are of and angiogenesis hallmark a is Angiogenesis 2008). al., for et mechanisms (Yudina important progression providing tumor thus for receptors and their inflammation and maintaining CysLTs both the including pathway, eicosanoid the CysLT upregulate extent, lesser uosi ie(unn,Kae,Sel,&Pria 02.M-8 a ensont euepancreatic reduce to shown been has or MK-886 MK-886, Genetic 2002). Zileuton, Pereira, TME. to & the Similar Steele, targeting Kramer, 2015). Malanchi, (Gunning, in results & mice promising efficient (Wculek in direct shown subsequent model be tumors a has reduced cancer has to inhibitor, breast and only FLAP demonstrated mouse activity not a a pro-metastatic been 5-LOX in neutrophils an of also metastasis inhibited Inhibition in lung has 5-LOX formation 2008). of but polyp al., inhibition cells et reduced pharmacological with Melstrom cancer Zileuton patients 2015; 2014). on in al., al., effect et tested et (Gounaris been (Knab models cancers yet multiple pancreas xenocraft not for and results has promising lung, (Haeggstr shown drug colon, APC has asthma this and of of studies disease, those inflammatory treatment animal airway in many including for investigated for in been States has effects effects United Zileuton beneficial promising cancer. the most had in the has marketed shown today Zileuton has is Zileuton and developed, targeting diseases, been at in have aimed leukotrienes have of that studies production Several inhibitors endogenous cancer. inhibit to to linked FLAP been or long 5-LOX have leukotrienes and pathway 5-LOX The drugs Anti-leukotriene of 4.1. potential investigated. therapeutic the been above, has described therapy pathways anti-cancer oncogenic for diverse signaling the CysLT on targeting CysLTs of MODELS effects CANCER the Given IN 2004). SIGNALING Lee, LEUKOTRIENE & CYSTEINYL Jin, TARGETING Park, 4. Kim, inflammation airway (Lee, attenuate expression to (Savari, VEGF postulated levels been reducing VEGF has by Montelukast tumor and reduce polymorphisms, and VEGF Sj cancer, by colorectal modulated & of Sime, model Zhang, xenograft Liu, mouse a in angiogenesis tumor ...Angiogenesis 3.3.7. 4 Δ468 idcdmdlo otcrn nignss(ue l,21) CysLT 2010). al., et (Xu angiogenesis ring aortic of model -induced ¨ om, uefrainadmgaino aclredteilclsadedteilcl irto suggesting migration cell endothelial and cells endothelial vascular of migration and formation tube os oe fplpssaddcesdtmrbre nLV n T9clncne murine cancer colon HT29 and LoVo in burden tumor decreased and polyposis of model mouse h,e l,2003). al., et Ohd, ¨ nvto n ehbvk ta. 06 alj auhr Sj & Paruchuri Sailaja 2006; al., et Mezhybovska yna r a M vitro( in lne,21) neetnl,tercgie niatmtceeto otlks is Montelukast of effect anti-asthmatic recognized the Interestingly, 2013). ¨ olander, ohLTC Both 1 ees hs eut ugs htiflmaoymdaoscnupregulate can mediators inflammatory that suggest results These levels, R 4 n LTD and 4 n LTD and , nvitro in 4 rmt nignssi an in angiogenesis promote 11 4 4 CsTRsgaigpooe niagoei action anti-angiogenic promotes signaling -CysLT2R nagoei Knys ta. 99.O h other the On 1989). al., et (Kanayasu angiogenis on and nvivo in nvivo in enovo de K86adZluo rvnslung prevents Zileuton and MK-886 . 1 acrmdl.Aogte5-LOX the Among models. cancer u olwo elgbeenzyme negligible or low to due eetratgnssas reduce also antagonists receptor 4 u o LTD not but - nvivo in 1 n CysLT and R hc chorioallantoic chick m 08.While 2018). ¨ om, ¨ lne,2003; olander, 4 2 stimulated - r both are R Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. 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(Nozaki CysLT capillaries capillaries, peripheral of peripheral vitro peripheral of antagonist and a in permeability and brain only in antiangiogenic the the migration metastasis novel both inhibiting cell tumor through inhibits by migration prevented Montelukast of cell metastasis antagonists whereas lungs tumor carcinoma These inhibit the lung 2004). can CysLT in Pranlukast Lewis al., Interestingly, 2002). expression of et al., VEGF (Lee model et regulating asthma mouse (Gunning al., by allergen-induced mice et permeability (Nozaki with in vascular mice mice tumors reduce in lung Montelukast model (Jose, metastasis carbamate-induced and rats carcinoma vinyl Pranlukast in lung carcinogenesis in Lewis mammary a and urea-induced in 2010), N-methyl 2013) N-nitroso Kumar, 2014). & in Sathyamurthy, al., 2013), Amathi, et al., (Magi et (Savari cells 2018), xenografts cancer al., skin et and (Piromkraipak few 2017) cells A pathways. al., glioblastoma different LTD et of through (Vinnakota of signaling proliferation cells invasion binding cell cancer and and the migration colon apoptosis cell blocks regulate suppress could that also CysLT LTRAs antagonist Suknuntha that CysLT1R 2018; suggesting al., 2006) selective et al., a (Piromkraipak cycle MK-5571, LTC cell Similarly, the not 2018). on action al., marrow its exerts et bone Zafirlukast of while neuroblastomas formation apoptosis, as CysLT colony induces well inhibiting et and as in growth (Suknuntha properties 2013), prevent breast pharmacological al., to 2017), failed et (Matsuyama Montelukast Savari al., urological However, 2006; CD34 2018). et including al., al., (Tsai et lines et Paruchuri lung (Zovko cell (S. 2007), cancer cells al., cancer human (Sveinbj colon et of and (Matsuyama series 2018), prostate al., a 2010), of CysLT Yoshimura, apoptosis above. & Several induce described 2016). and/or breast, pathways al., CysLTgrowth lung, oncogenic et on targeting especially (Tsai the of study development, manner potential on epidemiological cancer dose-dependent the of large a demonstrated risk in recent also cancers, the A liver decreased LTRAs. and LTRAs of some colorectal, that microenvironment, effect showed tumor-promoting chemopreventive the patients d.). and s. the asthmatic carcinogenesis Shimizu, investigated in & CysLTs Nakamura, have (Yokomizo, of rhinitis as studies prescribed role allergic known emerging widely and also the are asthma compounds, of that bronchial of Because Pranlukast, class of This management and decades. the Zafirlukast, two Montelukast, for than as drugs more such for CysLTs molecules market target the comprises to on “lukasts”, option been promising have most they the as certainly signaling are (LTRAs) antagonists receptor leukotriene (LTRAs) Cysteinyl antagonists receptor leukotriene Cysteinyl 4.2. LTC potent most the of one of is few effect permeability very TK05 the diseases, 2019). evaluated inflammatory have al., in studies 2009; role et Few LTC tumor central al., of its 1998). reducing et of Castonguay, despite inhibitors (Barry combination on & Indeed, cancers specific Rioux a effect pathway. skin CysLTs 2009; additive that and the Wang, shown breast an targeting & Fegn have specifically oesophageal, exhibits 2004; colon, studies inhibitor human al., Several FLAP of et xenografts Chen or 2014). model 5-LOX al., mouse a et in growth and (Knab inhibitor model cyclooxygenase hamster a a in growth cancer , + nvivo in xvivo ex CD38 rso ta. 08,gibatms(iokapke l,21) n hoi yli ekma(CML) leukemia myeloid chronic and 2018), al., et (Piromkraipak glioblastomas 2008), al., et ¨ ornsson 4 a ensont nii ooetlcne elpoieainbtntsria S auhr et Paruchuri (S. survival not but proliferation cell cancer colorectal inhibit to shown been has , - nvivo in tde aerpre h hmpeetv ffc fCsTRatgnssi ua oo cancer colon human in antagonists CysLT1R of effect chemopreventive the reported have studies ekmcse el rmCLptet Dlnk ta. 07.Atog TA aecommon have LTRAs Although 2017). al., et (Dolinska patients CML from cells stem leukemic and Kencmd ta. 05 u a o sytbe etdi acrmodels. cancer in tested been yet as not has but 2015) al., et (Kleinschmidt nvivo in 4 aebe eeoe ofr(lishite l,21;MnkA Rosensch Af Munck 2015; al., et (Kleinschmidt far so developed been have S oeso ooetlcne ihu agtn EFrcpos(ulre al., et (Butler receptors VEGF targeting without cancer colorectal of models 1 naoim npriua,Mneuat rnuat n Zafirlukast and Pranlukast, Montelukast, particular, In antagonism. R 1 n CysLT and R 1 inln,sm tde niaeta otlks mainly Montelukast that indicate studies some signaling, R 4 niiosrpre n infiatyrdcsvascular reduces significantly and reported inhibitors S 1 12 ahasfrat-acrteaydet t effects its to due therapy anti-cancer for pathways R 1 naoittetethsbe hw oinhibit to shown been has treatment antagonist R 2 a losonat-uo ffiayusing efficacy anti-tumor shown also has R nvitro in 1 antagonists R tde have studies 4 but ¨ old in Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. elmod,K,Sm,W,&Soadr .(05.Teipc fiflmaoylpdmdaoso colon on mediators lipid inflammatory of impact The (2015). A. Sjolander, cells. & cancer-initiating W., cancer. 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No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. CysLT distribution Tissue CysLT Receptor receptors leukotrienes cysteinyl of distribution Tissue 1. Table 2 1 CysLT R R 2 R aces-(yc ta. 1999), al., et (Lynch al., (P´erez-Novo et - - - Spleen - colon smooth and bronchial intestine Small Placenta valvular aortic Pancreas polyps Nasal goblet conjunctival Lung Heart smooth artery coronary Conjunctiva vessels Blood marrow bone and Blood mucosal bronchial mucosa Airway dea ln medullary marrow bone and Blood gland Adrenal 24 - macrophages alveolar cells, muscle myofibroblasts cells (HUVECs) cells endothelial vein umbilical human veins, saphenous cells, muscle platelets cells, dendritic -derived monocyte cells, mononuclear cells, mast lymphocytes), B cytes/macrophages, mono- neutrophils, (eosinophils, leukocytes blood Peripheral cells plasma and B-lymphocytes, macrophages, cells, mast neutrophils, eosinophils, edii el,platelets cells, dendritic monocyte-derived cells, mononuclear cells, mast monocytes), basophils, (eosinophils, leukocytes blood Peripheral cells ganglion pheochromocytes, Reference CysLT1R expressing Cells Srue l,1999) al., et (Sarau 2006) 1999) al., et (Lynch 2005), al., et (Zhu 2011) al., et (Nagy 2011) al., et (Dartt (L 2012), al., et (Eaton 2004), al., et (Mechiche 2012) al., et (Dannull 2010), al., et (Hasegawa 2003), al., et (Figueroa 1999), al., et (Lynch 2005), al., et (Zhu 2005) al., et (Zhu l,2005) al., et (Gauvreau 2000), al., et (Heise 2010), al., et (Hasegawa 2003), al., et (Figueroa 2000) al., et (Heise te ta. 2003) al., et ¨ otzer Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. aeoyCtgr iadVlePrmtreeecVlePrmtreeecVleParameterReference ParameterReferenceValue ParameterReferenceValue Value Agonists Agonists Ligand Category Category receptors leukotriene cysteinyl of Ligands 2. Table CysLT distribution Tissue Receptor 3 R LTC LTD 4 4 lo esl aclr n coronary and vascular, vessels Blood aiaygad Ib ta. 2004) al., et (Inbe al., et (Wittenberger 2004), al., et (Inbe 2000) 2004) al., al., et et (Heise (Inbe 2000) al., et (Takasaki - al., et (Adamusiak - mice) (in muscle 2000) smooth al., et and (Heise testis Kidney, - glands salivary lung) and - (trachea - tract Respiratory - placenta - kidney brain fetal and epithelial - muscle Spleen smooth airway Placenta polyps Nasal cells, Purkinje cardiac mucosa Nasal node Lymph goblet conjunctival Lung Heart Conjunctiva system nervous central and Brain 7.7 7.4- CysLT 9.4 7.3- 1 CysLT R a pEC 50 25 1 CysLT R 2019) al., et (B yL1 Reference CysLT1R expressing Cells (HUVECs) cells endothelial vein umbilical human veins, saphenous cells, muscle smooth artery H ta. 2004) al., et (He 2004) al., et (Inbe - basophils cells, mast cells glandular macrophages interstitial cells, fibroblasts myocytes, cells veins and arteries cerebral of cells muscle smooth cord, spinal and pituitary ¨ ack 1 CysLT R 8.6 7.0- 8.6 6.8- 2 CysLT R a pEC 50 (Sj 2005), al., et (Hu Mcih ta. 2004) al., et (Mechiche 2002) 2002) al., et (Wittenberger 2012) 2005) al., et (Corrigan 2000) al., et (Heise 2001) al., et (Kamohara 2000), al., et (Heise 2011) al., et (Dartt 2005) al., et (Hu 2000), al., et (Heise 2 CysLT R ¨ ostr 2019) al., et (B me l,2003), al., et ¨ om ¨ ack 2 CysLT R ------3 CysLT R 3 CysLT R 3 R Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. onist Antag- Antagonist onist Antag- Antagonist LTE [PMID:31811124] 13e compound 9773 u BAY- BayCysLT AI39---7,4- - - - HAMI3379 2570366) (ONO- Gemilukast 3465 CR- 31811124] [PMID: 15b compound 496 KP- 198615 [ 847) (MCC- Masilukast pK 7,8 Iralukast oiuat7,5- Pobilukast Montelukast8,3- 002 MN- 571 MK- 91507 MEN- 3 H]ICI- 4 2 CysLT 7.2 6.4- > 6,4 pA 5,3- 6,4 , pIC pK 5,8 5,3 pIC 6,9 ,4pA 8,64 pK 10,6 (Cuthbert, - - (Cabr´e 8,3 8,6 - pIC - 8 6,3 6,2- pIC 9 1 CysLT R pIC pIC pIC pK 2 2 i i d i c c c 50 50 50 50 50 50 50 d c f d c e e c,d c c 26 1 CysLT R 2015) al., et (Itadani 2004) al., et (Ferrari 2006) al., et (Ishimura 2019) al., et (B 2019) al., et (B 2002) al., et 2019) al., et (B 1991) al., et (Ohashi 1996) ¨ ack ¨ ack ¨ ack 1 CysLT R 7.1 5.6- 7,7 5,3- .-. pA 8.3-8.4 - - - - 8,4 pIC - 4,6 - pIC pIC 9.2 5,7 , pA 6,8 ------pK 5,2 ------pA - - - - 6,2 ------2 CysLT R pIC e pIC 2 2 2 d 50 50 50 50 50 d d d f d c e d 2 CysLT R - - - 5 2019) al., et (B 2019) al., et (B ¨ ack ¨ ack 2 CysLT R , pK 8,6 ------3 CysLT R b

3 CysLT R (Kanaoka tal., et 2013) 3 R Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. .Ca a. .against d. against c. [ b. assay tion liza- mobi- assay arrestin or assay tion liza- mobi- Ca LTD or LTC LTD or [ cells CHO in assay ing bind- 3 3 H]LTD H]LTE 2+ 2+ β - 4 4 4 4 4 assay tion liza- mobi- Ca 7,7- Zafirlukast 679) (MK- Verlukast 29878767] [PMID: 10 lator modu- triple uuat83pK pK 8,3 Sulukast 8,7 pIC SR2640 pIC 5,9 Quininib 8,1-10 Pranlukast assay arrestin or assay tion liza- mobi- Ca LTD or LTC against LTD or [ against cells CHO in assay ing bind- [ 3 3 H]LTD H]LTE 2+ 2+ β - 4 4 4 4 4 assay tion liza- mobi- Ca 9,6 8,1 8,0- pA 8,7 CysLT LTD or [ against assay arrestin or assay tion liza- mobi- Ca LTD or LTC against cells CHO in assay ing bind- [ 3 3 H]LTD H]LTE 2+ 2+ β - 4 4 4 1 4 CysLT R 4 pIC pIC assay arrestin or assay tion liza- mobi- Ca LTD or LTC against cells CHO in assay ing bind- [ 3 H]LTE 2+ 2 i i β 50 50 50 50 c - c c 4 4 c,d c d c 27 1 4 CysLT R 2019) al., et (B 2016) al., et (Reynolds assay arrestin or assay tion liza- mobi- Ca LTD or LTC against ¨ ack 2+ β - 4 4 1 CysLT R - - - - 5,2 - 5,1------pIC - pIC 5,9 5,4 assay arrestin or assay tion liza- mobi- Ca LTD or LTC against 2+ β - 4 4 2 CysLT R pIC 50 50 50 c,d d c 2 CysLT R 2019) al., et (B - - - 3 ¨ ack 2 CysLT R ------3 CysLT R 3 CysLT R 3 R Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. LTD Comments Pathways Function LTD Receptor cells cancer on CysLT receptors leukotriene cysteinyl of Effects 3. Table against e. LTD LTD LTD antagonist f. 4 4 4 4 4 CysLT uvvlPC-idcdrlclsto fvnui copne yaPCdpneturglto factive of upregulation PKC-dependent a by accompanied vinculin of relocalisation induced - PKC PKC 1. COX2, proliferation survival survival - - - onist antag- the by tion duc- pro- IP1 induced LTD4- parenchyma lung man hu- in assay ing bind- - 1 hmtxsPKC chemotaxis R onist antag- the by tion duc- pro- IP1 induced LTD4- against parenchyma lung man hu- in assay ing bind- antagonist survival proliferation CysLT onist antag- the by tion duc- pro- IP1 induced LTD4- against parenchyma lung man hu- in assay ing bind- antagonist 1 CysLT R / α onist antag- the by tion duc- pro- IP1 induced LTD4- against parenchyma lung man hu- in assay ing bind- antagonist β- ε- a- T-estv -rti nrae Akns rti xrsinvaaPKC a via expression protein MAPkinase increases - G-protein PTX-sensitive + Raf-1 COX2 1/2 MAPK/Erk- a--E12EK/ .Rs-atvtsEK12vaaPKC a via ERK-1/2 activates - Ras 2. Raf-1-MEK1/2-ERK1/2 aei,adBl2-icessepeso fCOX-2, of expression increases - Bcl-2 and catenin, 28 1 CysLT R onist antag- the by tion duc- pro- IP1 induced LTD4- against parenchyma lung man hu- in assay ing bind- antagonist eesItsia Int407 Intestinal levels protein Bcl-2 increases - pathway 1/2 MAPK/Erk- the of activation via expression COX-2 increases - 1 CysLT R 2 CysLT R cancer Colorectal 2 CysLT R Caco-2 2 CysLT R 2003) al., et (Wikstr 3 CysLT R ε/ β- a-/E-inln aha ciae a naprle eaaeptwyItsia n47(auhr ta. 2002) al., et (Paruchuri Int407 Intestinal pathway separate parallel a in Ras activates - pathway Raf-1/MEK-signaling ¨ om aei,Bl2-icessPE rdcin-ihbt S38idcdcs-eitdaotssItsia n47(h ta. 2000) al., et (Ohd Int407 Intestinal apoptosis cas3-mediated NS-398-induced inhibits - production PGE2 increases - Bcl-2 catenin, 3 CysLT R 3 R α n a- inln aha n T-estv hmtci epnet LTD to response chemotactic PTX-sensitive a and - pathway signaling Raf-1 and β nern n nacssbeun elahso oclae VItsia n47(asuiadSj and (Massoumi Int407 Intestinal IV collagen to adhesion cell subsequent enhances and integrins 1 4 elTp elln Reference line Cell Type Cell ooyi ekmaTP1(ohn ta. 1998) al., et (Hoshino THP-1 leukemia monocytic lne,2001) ¨ olander, Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. LTD PKC proliferation - LTD4 LTD 4 4 uvvlCsae8 Caspase survival - - uvvlPKC survival survival proliferation MEK/Erk Bid and ERK1/2/p90RSK / COX2 1/2 MAPK/Erk- Raf-1/ α/ 29 RB-increases - CREB process dependent PKC a in CREB activating by survival truncation Bid and activation 8 caspase lowering by inhibition COX2 by induced apoptosis prevents - process dependent 1/ERK1/2- / PKC a in protein Int407 p90 activating Intestinal by tion prolifera- increases - levels protein Bcl-2 increases - pathway 1/2 MAPK/Erk- the of activation via expression COX-2 increases - Raf- RSK α- netnlIt0 (Wikstr Int407 Intestinal (Paruchuri Int407 Intestinal 2003) Sj and 2003) al., et 2003) al., et (Wikstr ¨ olander, ¨ om ¨ om Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. LTD LTD LTD 4 4 4 CysLT proliferation - - 1 rlfrto in- - - proliferation R survival survival proliferation 1/2 PKC/Erk- 3 PI3K/Akt/GSK- COX2 1/2 MAPK/Erk- β 30 proliferation cell creases GSK-3 of rylation phospho- dependent PI3K- a by mediated Bcl2 protein survival cell with ciation asso- and Int407 nucleus the to tion Intestinal transloca- β- induces - levels protein Bcl-2 increases - pathway 1/2 MAPK/Erk- the of activation via expression COX-2 increases - catenin β netnlIt0 (Mezhybovska Int407 Intestinal cancer Colorectal ao2(Magnusson Caco-2 2006) al., et 2007) al., et 2003) al., et (Wikstr ¨ om Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. LTD LTC LTD 4 4 4 CysLT - CysLT 1 2 adhesion R differentiation R proliferation survival proliferation survival y 2 Pyk ERK/MAPK p44/42 COX2 1/2 MAPK/Erk- N tidase aminopep- and phatase phos- alkaline 31 proliferation induced cytokine- enhances - adhesion dependent integrin- and lates upregu- - Int407 Intestinal levels protein Bcl-2 increases - pathway 1/2 MAPK/Erk- the of activation via expression COX-2 increases - apoptosis induced butyrate- sodium enhances and activity 3 caspase increases - activity N tidase aminopep- of increase induced NaBT- enhances and activity phatase phos- alkaline increases markers: enciation differ- cell induces - α α 5 4 β β 1 1 cancer Colorectal tmclsCD34+ cells Stem cells progenitor poietic hemato- ao2(Magnusson Caco-2 2009) al., et (Boehmler 2003) al., et (Wikstr 2007) al., et ¨ om Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. LTD 4 CysLT - 1 migration R metastasis survival proliferation EGF/Rac1/Tiam1- COX2 1/2 MAPK/Erk- 32 expression Tiam1 increasing by activation Rac1 of wave induced EGF- second the regulates LTC4/LTD4 eesItsia Int407 Intestinal levels protein Bcl-2 increases - pathway 1/2 MAPK/Erk- the of activation via expression COX-2 increases - carcinoma Epidermal 41(aiet (Magi A431 l,2014) al., 2003) al., et (Wikstr ¨ om Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. LTD LTD 4 4 CysLT - 1 Proliferation R migration survival proliferation catenin GSK-3 COX2 1/2 MAPK/Erk- 33 β/β- phosphorylation) its (increases activity GSK-3 inhibits proliferation- and migration increases membrane- plasma the β- and E-cadherin of expression reduces : EMT induced CCND1- and MYC of transcription subsequent the and tion transloca- nuclear Int407 β- induces Intestinal - expression β- increases - levels protein Bcl-2 increases - pathway 1/2 MAPK/Erk- the of activation via expression COX-2 increases - aei at catenin catenin catenin β cancer Colorectal C-1 Slme al., et (Salim HCT-116 2014) 2003) al., et (Wikstr ¨ om Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. LTD LTD 4 4 CysLT - 1 stemness R proliferation survival survival proliferation COX-2 Bcl-3 Bcl-2 COX2 1/2 MAPK/Erk- 34 n 5-FU and radiation to resistance increases - cancer colon of model xenograft a in growth tumor -increases capacity formation colony increases - COX-2 of expression increases - Bcl-3 and Bcl-2 of expression gene Int407 increases - population Intestinal CICs ALDH+ increases - levels protein Bcl-2 increases - pathway 1/2 MAPK/Erk- the of activation via expression COX-2 increases - cancer Colorectal Caco-2 HCT-116, 2015) al., et (Bellamkonda 2003) al., et (Wikstr ¨ om Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. LTC LTD LTD 4 4 4 CysLT - CysLT 1 2 invasion R ieetainJNK/AP- Differentiation R migration survival proliferation MMP-9 β- COX2 1/2 MAPK/Erk- 1 catenin 35 invasion increases - β- of tion transloca- tion/nuclear (stabiliza- markers Int407 EMT induces - Intestinal MMP-9 of expression increases - levels protein Bcl-2 increases - pathway 1/2 MAPK/Erk- the of activation via expression COX-2 increases - expression COX-2 lates downregu- - mucin-2 and isomaltase sucrase- markers entiation differ- of expression increases - rylation phospho- 1 JNK/AP- via 15-PGDH suppressor tumor lates upregu- - catenin) cancer Colorectal cancer Colorectal W8 (Vinnakota SW480 T2 (Mehdawi HT-29 2017) al., et 2003) al., et (Wikstr 2017) al., et ¨ om Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. LTD LTC LTD 4 4 4 yL1 eaoim--upregu- - - metabolism CysLT1R - CysLT 2 survival R survival proliferation migration COX2 1/2 MAPK/Erk- VEGFR MMP-2/9 3 Caspase Bcl-2 β- catenin 36 expression CysLT2R and CysLT1R increases expression- COX-2 lates Int407 Intestinal levels protein Bcl-2 increases - pathway 1/2 MAPK/Erk- the of activation via expression COX-2 increases - levels VEGFR-1 and -9, and MMP-2 decreases - manner dependent TNF a in 15-PGDH induces - Caspase-3 activates and Bcl-2 lates downregu- β- rylates phospho- - aei - catenin α netnlIt0 Ydn et (Yudina Int407 Intestinal cancer Colorectal Caco-2 HT-29 l,2008) al., 2003) al., et (Wikstr 2018) Sjolander, and (Satapathy ¨ om Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. LTD LTD 4 4 CysLT - 1 namto G- increases - EGR-1 Inflammation R survival proliferation COX2 1/2 MAPK/Erk- 37 expression EGR-1 factor scription tran- of induction via CCL4 and CCL-3 IL-8, IL-6, TNF- expression CysLT2R increases and expression CysLT1R decreases - expression LTC4S and 5-LOX increases - eesItsia Int407 Intestinal levels protein Bcl-2 increases - pathway 1/2 MAPK/Erk- the of activation via expression COX-2 increases - α, lymphoma Hodgkin cancer Colorectal KMH2 L1236 HCT-116 SW-480, HT-29, Caco-2, l,2015) al., et (Han 2008), al., et (Schain 2003) al., et (Wikstr ¨ om Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary. iue2 oeo ytiy ektinsi carcinogenesis. in leukotrienes cysteinyl of Role 2. Abbreviations: GGT, Figure GGT. protein; or protein. 5-lipoxygenase-activating LTC4S resistance-associated FLAP, multidrug 5-LOX, cPLA2 dipeptidase; MRP, of acid; DPEP, transpeptidases; arachidonic expression A2; AA, the phospholipase 5-lipoxygenase; red) tosolic 5-LOX, (in acid; downregulate 5-hydroperoxyeicosatetraenoic or pathway.5-HPETE, green) leukotriene (in cysteinyl upregulate the affinity. binding of receptor/ligand zymes LTC the space, represents extracellular arrows the In CysLT 4. and 1 LTE to MRP by exported LTAis to converted further cPLA LTA Ca the class, intracellular of two metabolites into and leukotrienes. divided cysteinyl enzymes are Key leukotrienes A. The biosynthesis. and cascade structures leukotriene Leukotrienes, 1. Figure LEGENDS FIGURE LTD LTD 4 4 2 2 α 4 hra P9,o CysLT or GPR99, whereas R eessmmrn hshlpd opouefe Awihi rsne o5LXb LPand FLAP by 5-LOX to presented is which AA free produce to phospholipids membrane releases yDE.Csenlluoree LTC leukotrienes Cysteinyl DPEP. by specified not - 2+ sicesdlaigt rnlcto fcPLA of translocation to leading increased is Ai ovre y5LXi ojnto ihFA noLTA into FLAP with conjunction in 5-LOX by converted is AA .Boyteiptwyo ytiy leukotrienes. cysteinyl of Biosynthesispathway B. 4 LTA . metabolism survival proliferation 4 scnuae ordcdguahoeb T4 ofr LTC form to LTC4S by glutathione reduced to conjugated is 3 ,i eetrwt ihant oLTE to affinity high with receptor a is R, β- COX2 1/2 MAPK/Erk- 4 aei increases - catenin n LTD and 4 eaoie uha LTB as such metabolites H 38 aiu yoie n oeue aebe hw to shown been have molecules and cytokines Various .Rglto fteepeso fteen- the of expression the of Regulation C. 4 a idt w ao eetr CysLT receptors major two to bind can NF- quent subse- and levels ROS increases - tion accumula- β- via genes mtDNA of tion Int407 transcrip- and ratio Intestinal ATP/ADP NADPH, levels protein Bcl-2 increases - pathway 1/2 MAPK/Erk- the of activation via expression COX-2 increases - 4 catenin scnetdt LTD to converted is 2 κ α B n -O otencermembrane. nuclear the to 5-LOX and netnlIt0 (Mezhybovska Int407 Intestinal 4 pnclua stimulation, cellular Upon n T4 metabolites, LTC4S and 4. 4 h hcns fthe of thickness The 4 yGTadLTD and GGT by hog 5-HPETE. through γ- glutamyl 4 which , 1 and R α, cy- 4 2009) al., et 2003) al., et (Wikstr ¨ om Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986479.93555251 — This a preprint and has not been peer reviewed. Data may be preliminary.       
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