Posted on Authorea 25 Feb 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161425406.62861504/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. fbt ye fcne el eeicesdb eouae(cmvc cuh ury oa,&Buggy, migration & the migration Doran, increased and Murray, sevoflurane McHugh, that proliferation demonstrated (Ecimovic, the sevoflurane laboratory and by our sevoflurane, from increased publication were to previous cells exposed An cancer were an 2013). of cells In types anaesthesia cancer and death both anaesthetics 2015). breast of of of Ben-Eliyahu, choice negative cause the & or be leading may Sharon, positive them a of Neeman, one still (Horowitz, and is recurrence, techniques Audisio, cancer (Wyld, surgery affect 2011). effective factors following very risk al., Many ovarian recurrence be et Zhu can for cancer 1996; stage treatments ovarian Gray, early The However, more & the Tormey, and at (Saphner, 2018). resection 2015). cases al., therapy tumour new Poston, frontline the et the 295,000 & as (Bray remains patients, than surgery globally 2018 cancer them, more mortality ovarian in Among estimated for seventh-highest worldwide radiotherapy. and an the cancer chemotherapy, surgery, were ovarian and include There of cancer cancer deaths diagnosed 2005). 184,000 frequently Pisani, than most & Ferlay, sixth Bray, the (Parkin, is cancer Ovarian warrants work this of Introduction value translational The property. were anti-tumour an metabolites afford those enhanced might of study. sevoflurane propofol changes further propofol, but opposite unlike property that the indicated pro-tumour PEDF/Erk/HIF-1 but activated data have media, and These metabolism the Implications: cell in and levels cancer Conclusion increased ovarian levels Sevoflurane glutamine treatment. propofol. propofol and with after glucose observed found were decreased markers but cellular increased isopropanol these HIF-1 Sevoflurane proliferation, of of viability, changes” propofol. and by “mirror cell p-Erk1/2, suppressed the The treatment, but GLUD1, sevoflurane sevoflurane Results: by MPC1, enhanced Key were GLUT1, cells and analysis. the cancer healing ovarian metabolomics wound of spectroscopy-based invasion Cultured staining, and 1H-NMR blot. Ki-67 migration, Western for and/or kit-8, staining collected counting immunofluorescent were cell using measured media using were hypothesised assessed biomarkers was signalling were 4 Cellular cells invasion it and assay. cancer with and Transwell study, ovarian metabolism administered migration Cultured current cellular proliferation, or Approach: viability, the sevoflurane Experimental cancer factors cell In 2.5% cells. affect risk cancer to might ovarian perioperative surgery. exposed of propofol However, malignancy after were anaesthetic the recurrence interfere intravenous cancer. might its and which ovarian signalling, influence sevoflurane of may anaesthetic treatment anaesthetics inhalational first-line that of the choice remains the Surgery including Purpose: and Background Abstract 2021 25, February 2 1 Lian Qingquan Hu Cong signalling and mechanisms metabolic cellular cell regulating cancer through ovarian malignancy enhances propofol not but Sevoflurane meilCleeLondon College Hospital Affiliated Imperial Second University Medical Wenzhou 1 icegWang Bincheng , 1 u li jun , 1 i Li Jia , 2 hgn Liu Zhigang , 2 n aigMa Daqing and , α xrsin u erae h EFepeso.I otatt the to contrast In expression. PEDF the decreased but expressions 2 iigChen Qiling , μ /Lpooo o or olwdb 4husrcvr.Their recovery. hours 24 by followed hours 2 for propofol g/mL 1 α ellrsgaln aha,sgetn htsvflrn might sevoflurane that suggesting pathway, signalling cellular 2 2 aah Ishikawa Masashi , nvitro in td,osrgnreceptor- oestrogen study, 2 a Lin Han , 1 , Posted on Authorea 25 Feb 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161425406.62861504/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. o or.TeO auso acrclswr eetda aeegho 5 m C- ouinwith solution (treatment) staining [OD CCK-8 Ki-67 to nm. 100%. with equalled X 450 assessed values (blank)] of was viability OD wavelength proliferation Cell – a 37 Cell blank. (control) at at as [OD detected used solution / were was (CCK-8) (blank)] cells cells OD kit-8 cancer cancer - counting without of cell but values plus media OD media culture The with hours. incubated 4 were for media. cells fresh SKOV3 in recovery, assay recovery Cruz After CCK-8 hours (Santa with 24 control) 4 by assessed followed was (vehicle UK), and viability intralipid Sittingbourne, hours, Cell serum 2 or (ABOTT, bovine for (na¨ıve control), sevoflurane USA) media foetal 2.5% Texas, Dallas, UK), 10% with Biotechnology, 37 Dorset, administered with at were (Sigma-Aldrich, supplemented UK) cells propofol UK) Paisley, SKOV3 Paisley, cultured (ThermoFisher, air. were (ThermoFisher, penicillin-streptomycin with cells SKOV3 1% 1640 UK). and media (Wiltshire, (FBS) ECACC RPMI from purchased Gibco was (SKOV3) in line cell cancer Ovarian culture Cell and sevoflurane increased as HIF-1 such The cells. p-Erk1/2, anaesthetics cancer upregulates by ovarian Methods cells. entities turn, of cancer molecular malignancy in and the ovarian and, change metabolism expressions of PEDF might of the metabolism of propofol alterations upregulate expression the The might the increases CXCR4. sevoflurane and inhibits which propofol, glucose GLUD1, types, unlike of cancer and that uptake of MPC1, hypothesised variety 2020). GLUT1, we a al., study, of in et current overexpressed (Scala (CD184) was tumours the 184 CXCL12-CXCR4 of differentiation In progression of that called the receptor cluster found also or its in was involved (CXCL12), fusin and It is as leukocytes 12 named and of 2014). chemokine also activity al., (CXCR4), the motif 4 et with C-X-C type (Takano correlated receptor de originally chemokine malignancy. is Nelius, C-X-C HIF-1 cancer (SDF1), is (Filleur, 1 ovarian of cancer factor signalling the cell-derived and upstream the in stromal disease the is involve heart regulators Besides also neovascularisation, these might choroidal 2009). of Kennedy, for therapeutic one The & found and family. Riese, were inhibitor Erk1/2 protease PEDF of serine 2014) pathway the of Ma, of signalling values member & a the HIF-1 Savage, (PEDF), regulate Yang, factor regulate epithelium-derived can Iwasaki, pigment can regulators (Zhao, pathway Several cancer Erk1/2 lung signalling 2019). and cellular the colonic the in breast, whilst locates including (HIF-1 types, that alpha interfere tumour enzyme may factor-1 many key activity hypoxia-inducible and factor the expression transcriptional is al., 2013). GLUD1 The GLUD1 et al., for the et (Craze which affect (GLUD1) survival (Son that for survival 1 and factors glutaminolysis cell growth Any dehydrogenase cancer as cancer mitochondria. glutamate for named of of intermediates is membrane crucial catalysation inner Glutamine process generates the 2019). Such which al., under cycle et 2019). glutamate TCA Zou pyruvate, 2020; the be to Carico, in to & transformed using Pagliuca, and transformed Ricci, (GLUT1) D’Ascanio, be (Pezzuto, 1 can cycle transporter TCA mitochondria by glucose enters utilised through than be rather cells lactate cancer to al., converted by et is which (Enlund up anaesthesia taken propofol is unknown. with Glucose are higher mechanisms were or underlying rates colonic the survival breast, However, five-year the anaesthesia and 2014). inhalational for one-year sevoflurane surgery or overall had anaesthesia their who intravenous total et patients, and previous propofol-based (Huang that our under cells reported example, were cancer study cancer, for prostate retrospective rectal of property; a migration “anti-tumour” Clinically, and an proliferation 2014). have the al., to inhibited propofol reported that was demonstrated propofol study contrary, In 2016). al., cells cancer ovarian of via upregulating EF,MP1 CXCR2, MMP11, VEGFA, 2 via iohnra yuaecrir1(P1 to (MPC1) 1 carrier pyruvate mitochondrial α α ly e oeo h eeomn of development the of role key a plays ) and Krgoa ori io,&Mylonis, & Simos, Kourti, (Karagiota, α, h ontemeetr fHIF-1 of effectors downstream the ΤΓΦ-β ° ih5 CO 5% with C eeepesos(wsk et (Iwasaki expressions gene 2 n balanced and α, CXCL12, μ g/mL ° C α Posted on Authorea 25 Feb 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161425406.62861504/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. %nnftml o oradicbtdwt rmr nioya 4 with at blocked antibody primary was was with membrane gel incubated The the and UK). hour on Paisley, 1 protein (ThermoFisher, for (ThermoFisher, the milk buffer membrane electrophoresis, non-fat sample After nitrocellulose 5% LDS electrophoresis. a NuPAGE for to UK) with UK) London, transferred Paisley, 95 Technology, mixed (ThermoFisher, at signalling were gel (Cell samples boiled Tris buffer protein and lysis The UK) cell Paisley, with proteins. adapted extract were to cells SKOV3 recovery, After HIF-1 and Erk1/2, analysis p-Erk1/2, blot PEDF, of GLUD1, expressions MPC1, The microscope. GLUT1, cells. fluorescence cancer a on by mounted detected were After were USA) minutes. proteins California, 30 Burlingame, for Laboratories, times ( (Vector UK) sequence 3 media 4 Dorset, in UK) at dark (Sigma-Aldrich, Dorset, under antibody serum (Sigma-Aldrich, temperature primary donkey room X-100 with 10% Triton incubated with 0.02% were blocked cells plus and blocking, PBS each with minutes USA) washed Texas, 5 were Dallas, Biotechnology, for Biotechnology, Cells Cruz Cruz (Santa minutes. (Santa paraformaldehyde 15 4% (PBS) in for saline incubated phosphate-buffered and with USA) Texas, washed Dallas, were cells SKOV3 recovery, After as 2.0) regarded (ImageJ were staining Fiji HIF-1 with it PEDF, violet counted of USA). MPC1, was crystal membrane Maryland, cells GLUT1, invasive Bethesda, 0.1% bottom upper of Health, the the with number of on on The dyed Institutes cells microscope. cells were The (National a The dye. software chamber by leftover removed. detected the upper were and away chamber the cells get invasive upper to on washed the After cells and of minutes kit. cancer membrane 15 assay for The upper Transwell UK) minutes. the the Dorset, of 30 (Sigma-Aldrich, in New chamber seeded for lower (Corning, and UK) the matrix Paisley, media into Matrigel 37 placed Corning FBS-free at was with with media pre-embedded incubated mixed was FBS-enriched were which The kit, cells USA). assay York, 4 cancer Transwell or administration, sevoflurane, the 2.5% of After media, chamber with administered hours. and 2 dishes petri for in seeded were cells SKOV3 assay Transwell the USA). with with hours, cells Maryland, cancer assessed 24 Bethesda, of was for Health, capability invasion media of migrate Cell cell-free culture the Institutes The with calculate (National to incubated cells. software microscope cancer After 2.0) the suspended (ImageJ baseline. under discard Fiji the again to captured as PBS was microscope with gap washed a cell-free were under pure dishes captured in petri incubated was The were gap cells gap. Cancer cell-free monolayer. continuous a 4 a form or form sevoflurane, to dishes 2.5% petri media, in seeded Bethesda, were assay of cells Health, healing SKOV3 percentage wound of with the Institutes assessed (National and was software migration microscope 2.0) Cell fluorescence (ImageJ under Fiji 4’,6-diamidino-2- taken by mounted The calculated USA). were were Maryland, sequence. was images USA) in cells fluorescent California, dark positive for The Burlingame, under Ki-67 UK) cells. temperature Laboratories, Dorset, cancer (Vector room (Sigma-Aldrich, media on at serum mounting (Santa hour polyclonal) (DAPI) 1 donkey rabbit phenylindole for 10% (1:200, UK) with antibody Cambridge, anti-Ki-67 4 blocked (Abcam, Dorset, with at and USA) (Sigma-Aldrich, incubated Texas, Texas, X-100 were each Dallas, Triton Biotechnology, Dallas, cells Cruz minutes 0.02% Biotechnology, blocking, plus 5 After Cruz PBS minutes. for with (Santa 30 washed times paraformaldehyde were 3 cells 4% Cancer UK) Biotechnology, in minutes. Cruz 15 incubated (Santa for (PBS) and USA) saline USA) phosphate-buffered with Texas, washed Dallas, were cells SKOV3 recovery, After ° o 4hus h pe hme a netdi h 0 ehnl(ThermoFisher, methanol 70% the in inserted was chamber upper the hours, 24 for C μ α, ° /Lpooo o or.Temnlyro acrclswssrthdto scratched was cells cancer of monolayer The hours. 2 for propofol g/mL o 0mnts h oldsmlswr oddot uAEBis- NuPAGE a onto loaded were samples boiled The minutes. 10 for C XL2 n XR xrsin eedtce ihimmunofluorescent with detected were expressions CXCR4 and CXCL12, al S1 Table ° vrih n nirbi nioy(:00 otpolyclonal) goat (1:1000, antibody anti-rabbit and overnight C .Te4,-imdn--hnlnoe(AI mounting (DAPI) 4’,6-diamidino-2-phenylindole The ). 3 ° vrih n eodr nioyfr1hu at hour 1 for antibody secondary and overnight C α xrsin eedtrie ihWestern with determined were expressions ° vrih n eodr antibody secondary and overnight C μ /Lpropofol g/mL Posted on Authorea 25 Feb 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161425406.62861504/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ple oacquire to applied h irt aaiiyo vra acrclsatrsvflrn ramn a infiatygetrta that than greater significantly was treatment sevoflurane (NC after treatment cells propofol cancer ovarian by of decreased capability significantly migrate The were cells positive Ki-67 However, 32.0 (NC 6). administration = sevoflurane ( n by cells 0.01, increased positive significantly Ki-67 was of cells number the by indicated (NC na¨ıve control to compared of vs viability cell cells cancer cancer ovarian 100.0 ovarian the in increased malignancy significantly cancer Sevoflurane on propofol or sevoflurane of Effects antibody Rheinstetten, anti-GAPDH Corporation, The Bruker Results UK. from was London, tube Technology, NMR signalling The and UK. Cell analysis, Germany. Hertfordshire, from blot Merck, Western from acquired for purchased were was antibodies buffer anti-mouse USA. York, and lysis anti-rabbit New cell Corning, antibodies, anti-Erk1/2 from and purchased Laboratories, was Vector p-Erk1/2 from matrix anti-HIF-1 acquired and Matrigel was anti-MPC1 Corning were media The The mounting antibodies USA. DAPI immunoflu- anti-CXCR4 The California, for from and UK. Burlingame, antibodies Cambridge, were anti-CXCL12 anti-mouse Abcam, anti-PEDF, solution and from reagent anti-GLUD1, anti-rabbit obtained luminol anti-GLUT1, The USA. and staining, Dorset, Texas, antibody orescent Sigma-Aldrich, Dallas, anti-Ki-67 from Biotechnology, acquired paraformaldehyde, Cruz were violet PBS, Santa crystal intralipid, and The serum membrane Sittingbourne, donkey ABOTT, UK. nitrocellulose penicillin- X-100, from Triton purchased 1640, and was propofol, media sevoflurane gel The The RPMI Bis-Tris UK. UK. NuPAGE Gibco Paisley, ThermoFisher, The buffer, from UK. obrained sample Wiltshire, were LDS ECACC, NuPAGE from methanol, purchased was streptomycin, line cell SKOV3 The Edmonton, (CHENOMX, Senn, software method & Materials Chenomx alignment using Schlotterbeck, peak identified segment-wise Ross, and were recursive (Dieterle, Metabolites 5.0, with method to 2009). aligned Canada). was al., normalisation 4.7 data et quotient from Veselkov spectral probabilistic ranged 2006; The shift with cut. chemical (Sartorius, normalised was The SIMCA and data 0.3 and to analysis. spectral USA) -1 The statistical Massachusetts, from ppm. multivariate Natick, Germany). 20 for of (MathWorks, Rheinstetten, Germany) width R2018a Corporation, spectral Gottingen, MATLAB a (Bruker into with 4.0.9 points imported TopSpin data were k using 64 acquired into t were collected and were data s media 4 cell of for delay scans delay-90 recycle 32 (recycle a during sequence irradiation pulse selective NMR using standard A K. 300 operating of the temperature at a Germany) mm. Rheinstetten, Corporation, 5 (Bruker of spectrometer diameter outer 540 an with 580 sample media of The experiment, total NMR temperature. the room before day the One μ at collected. were thawed cells were spectroscopy SKOV3 of samples NMR media proton culture with Institutes the recovery, measured (National After were software media 2.0) in (ImageJ alterations Fiji (Syngene, metabolic by The 7.1 analysed Version USA). were GeneSnap Maryland, protein by Bethesda, of detected Health, levels were of the bands and protein UK) The Cambridge, USA). Texas, ( Dallas, Biotechnology, day next the on oasu hsht ue p .)cnann . KH M 1.5 containing 7.4) = (pH buffer phosphate potassium L ,100.0 S, . ± ± 5.1 1.5 vs vs μ ± itr a lcdit nNRtb Bue oprto,Rentte,Gray with Germany) Rheinstetten, Corporation, (Bruker tube NMR an into placed was mixture L 16.0 . 122.0 . 1.5 al S1 Table 1 -M pcrldt (t data spectral H-NMR vs ± ± .,p 7.3, 61.6 . .,p 4.1, o oradaatdwt uio egn ouinAadB(at Cruz (Santa B and A solution reagent luminol with adapted and hour 1 for ) < ± 1 < α -M pcr fmdasmlswr banduigaBue 0 MHz 600 Bruker a using obtained were samples media of spectra H-NMR .5 )( 6) = n 0.05, .,p 5.4, nioiswr bandfo ou ilgcl,Aigo,U.Teanti- The UK. Abingdon, Biologicals, Novus from obtained were antibodies .01 ) hl rpflsgicnl erae h elvaiiy(NC viability cell the decreased significantly propofol while 6), = n 0.0001, < .01 )( 6) = n 0.0001, 1 3 = i 1C Fig μ i 1B Fig ,t s, m 4 ). 0 s.Tewtrpa upeso a achieved was suppression peak water The ms). 100 = .I a on httenme fK-7positive Ki-67 of number the that found was It ). i 1A Fig m 90 A . 2 PO º .Tepoieaino KV el was cells SKOV3 of proliferation The ). vs us a dutdt ˜10 to adjusted was pulse 4 m NaN 1mM , ,32.0 S, . μ a olce n ie ih60 with mixed and collected was L º -t 1 rqec f601 H at MHz 600.13 of frequency H 1 -90 ± 3 º 5.1 .%TPadD and TSP 0.1% , -t m vs -90 52.4 . º 1 -M spectral H-NMR custo)was acquisition) μ .Attlof total A s. ± 38 p 13.8, vs vs 2 .A O. P, . S, . < Posted on Authorea 25 Feb 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161425406.62861504/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. h irt aaiiyo acrclswsihbtdb rpflepsr (NC exposure propofol by inhibited was cells cancer ± of capability migrate the rmWsenbo nlss twsas on htteepeso ee fHIF-1 of HIF-1 level of expression intensity the lower that found a also had was (HIF-1 group it 1-alpha analysis, propofol factor blot the hypoxia-inducible Western From of of intensity those higher while a na¨ıve control, had (NC sevoflurane group with sevoflurane administered the in increased 1.0 significantly was Erk1/2 to vs p-Erk1/2 of (NC ratio level exposure propofol after (NC ( higher exposure significantly na¨ıve sevoflurane to but after compared 6) group PEDF propofol of the level in epithelium-derived expression increased pigment but of group sevoflurane intensity ( the fluorescent control in the decreased that was HIF-1 found (PEDF) and factor pathway, was Erk it expression, staining, immunofluorescent PEDF From on propofol arginine, or acetone, ( sevoflurane succinate, ethanol of asparagine, of Regulations acids, level Fur- fatty the propofol. glycerol, and decreased of sevoflurane but levels propofol both isoleucine, by the the and increased increased in were also decreased leucine propofol and was thermore, valine, isopropanol alanine, of ( acetate, pyruvate, group concentration control lactate, ( the vehicle to and group contrast na¨ıve increased increased, control in was group the were isopropanol to glutamine of compared and concentration the glucose group and sevoflurane decreased, the were glutamine in group and sevoflurane glucose and na¨ıve of control between concentrations separations clear were there ( showed models R plots both scores with showed OPLS-DA together values The values p p Permutation permutation component. The orthogonal one na¨ıve and control of component predictive one ( plot with groups scores PCA four The these components. among principal vs pattern 2 grouping with propo- analysis clear and PCA sevoflurane, a control, unsupervised showed na¨ıve vehicle using control, of analysed cells were samples SKOV3 groups media of fol from metabolism obtained profiles cellular metabolic the The on propofol or sevoflurane of Effects ( na¨ıve control the (NC to administration compared treatment (NC propofol administration sevoflurane after decreased significantly F were 6) = n (NC GLUT1 of than vs group levels propofol expression the protein in the lower much analysis, but na¨ıve blot 0.1 control, cells to Western ( cancer compared From ovarian GLUT1 na¨ıve group control. of in sevoflurane the intensities GLUD1 the the and in cells, MPC1, higher of were GLUT1, staining immunofluorescent of the expressions on the Based on propofol or sevoflurane of Effects in observed was ( cells 6) invasive (NC of na¨ıve control number to higher ( compared Significantly group assay. Transwell sevoflurane with the cells invasive of number (NC na¨ıve control the of infiatyicesdatrsvflrn exposure sevoflurane after increased significantly i 4D Fig 3B Fig 1F Fig .Smlry h xrsinlvlo ltmt eyrgns GU1 a infiatyicesdby increased significantly was (GLUD1) 1 dehydrogenase glutamate of level expression the Similarly, ). .,p 9.4, ,1.0 P, . vs 1.3 . eouaegopadvhcecontrol vehicle and group sevoflurane . ± i 1G Fig 1.4 . 0.1 ± i 4A Fig ,weespooo xiie nopst ffc (NC effect opposite an exhibited propofol whereas ), ,advhcecnrladpooo ru ( group propofol and control vehicle and ), < vs .Dffrn rmPD xrsinlvl,teWsenbo nlsssoe htteexpression the that showed analysis blot Western the levels, expression PEDF from Different ). ± .,p 0.2, ± .1 )( 6) = n 0.01, ). 0.7 . 0.1 .,p 0.3, vs vs .Tersl a aiae sn etr ltaayi,wihsoe h infiatylower significantly the showed which analysis, blot Western using validated was result The ). < ± 0.3 . eouae( .0)advhcecontrol vehicle and 0.005) = (p sevoflurane . .5 ) u erae ntepooo ru oprdt h oto (NC control the to compared group propofol the in decreased but 6), = n 0.05, < .,p 0.2, vs .1 )adMC (NC MPC1 and 6) = n 0.01, ,1.0 P, . ± vs i 1E Fig < .,p 0.1, ,55.2 S, . .5 )( 6) = n 0.05, ± vs < 0.1 ,1.0 S, . .Teivso foaincne el a vlae ycmaigthe comparing by evaluated was cells cancer ovarian of invasion The ). .01 )adMC (NC MPC1 and 6) = n 0.0001, vs ± 0.6 . 7.5 i 3E Fig i 4E Fig ± 2 vs ,Q X, vs 0.1 ± rpflgopwr are u sn PSD analysis OPLS-DA using out carried were group propofol . .,p 0.2, 92.5 . 2 vs Fg2C (Fig ,adQ and X, .Atraashtc diitain h ocnrtosof concentrations the administration, anaesthetics After ). al 2 Table .Smlry h ursetsann hwdSO3cells SKOV3 showed staining fluorescent the Similarly, ). i 3D Fig 1.4 . vs 5 < ± vs ,1.0 S, . vs ± .0,n=6 ( 6) = n 0.001, .,p 8.2, ,1.0 S, . vs i 3A Fig .Hwvr h xrsinlvl fGU1(NC GLUT1 of levels expression the However, ). 2 .,p 0.1, .TeOL-Alaig lt hwdta the that showed plots loadings OPLS-DA The ). ,1.0 P, . ). ftomdl eesmaie ( summarised were models two of Y ,1.0 S, . vs ± vs < i 3C Fig ,1.0 P, . < ± 0.3 vs .01 )( 6) = n 0.0001, .Pi-iecmaioso na¨ıve control of comparisons Pair-wise ). rpfl( .0)hdsignificances. had 0.005) = (p propofol . ± .1 ) u erae ypropofol by decreased but 6), = n 0.01, 0.1 ± ,1.0 P, . vs 0.1 i 2D Fig 0.1 vs ± 1.5 . .Hwvr h ocnrtosof concentrations the However, ). vs 0.1 2.2 . vs i 2A Fig ± 1.2 . ± 0.6 . vs α 0.3 ). vs α .,p 0.2, ± a infiatyincreased significantly was 0.4 . hncnrl( control than ± vs .,p 0.6, ,55.2 P, . i 1D Fig ± n P1( MPC1 and ) α .,p 0.1, 0.6 . .,p 0.2, ± expression < .,p 0.1, .1 )were 6) = n 0.01, < vs ± < .01 6) = n 0.0001, ± < .I contrast, In ). .,p 0.3, ,1.0 S, . vs i Eand 2E Fig .5 6) = n 0.05, < .01 = n 0.0001, 7.5 α al 1 Table i 4B Fig hnthe than ) ,1.0 S, . i 2B Fig .5 = n 0.05, vs < vs 34.3 . ± 0.05, P, . 0.1 ± ). ). ) Posted on Authorea 25 Feb 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161425406.62861504/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. yTAccet etr h uvvlo acrclsa h nemdae fTAcceaetesuc for source the & are Sung, Yu, cycle (Yoo, TCA acids of nucleic used uptake intermediates and be turn, skeleton, the can in carbon as glutamate lipids, cells, cells acids, The cancer cancer fatty GLUD1. and of proteins, of intake survival acids, pyruvate activation the amino less the restore of to under synthesis to due glutamate cycle from cycle compensates into TCA cells shifts of glutaminolysis TCA by them cancer addition, likely rate the as convert In pyruvate supply of high and 2016). oxygen that function a glutamine Taylor, require suggests & disturbed under not (Rauckhorst This the those does condition which for glycolysis. especially hypoxic glycolysis, of under types cytoplasm usually rate tumour to (Taylor,are cycle increased most cytoplasm TCA in the at from mitochondrial decreased to locates the mitochondria was is related system, into media MPC1 pyruvate as carrier in of transports proliferation mitochondrial glutamine expression and of exposure The of mitochondria sevoflurane member of 2017). concentration after a membrane upregulated the MPC1, were inner Besides, administration. GLUD1 the treatment. and sevoflurane propofol MPC1 after of after decreased expressions study. downregulated current the were our both but of that 2010). findings that found Klein, the & was reported with (Horn It was levels line lactate It in (S and be were pyruvate lactate. dogs might increased reports of more sevoflurane these blood which that generated the All demonstrated treatments, in then also level propofol mice lactate and in and the glycolysis study increased sevoflurane both in both propofol pyruvate and in increased sevoflurane increased the was from expression lactate resulted the of to related concentration was cells The Hau, cells cancer cancer & rate, administration. ovarian O’Neill, proliferative of anaesthetic Shen, high malignancy after (Mudassar, the under GLUT1 condition that as, of hypoxic findings scenario, under our cell preconditioning actually supported hypoxic cancer were These under to 2020). and tissue similar supply brain quite oxygen rat is inadequate (Wright, the This in had glycolysis proteins 2020). of GLUT1 al., rate of et high al., downregulation (Xiao the the et uptake for with Pezzuto downregulate essential line glucose 2004; to were in (Leung, cellular was cells reported cancers cancer was The of and in Propofol malignancy exposure. GLUT1 media, the 2020). of from propofol with overexpression glucose correlated after the of was and increased expression uptake 2020) was GLUT1 less of glucose the level in of administration. high sevoflurane resulted concentration after after which media the cytoplasm found GLUT1, the the upregulated hence in downregulated into were changes observed glucose propofol media metabolic more with contrast, the transport the agreement explained In may which GLUT1 in in pyruvate, of to pyruvate activity were convert enhanced which to of The na¨ıve control, GLUT1. concentration of the higher level to expression and compared glucose exposure uptake of sevoflurane the concentration glutamine. enhancing and by lower glucose cells The cancer as ovarian such of substrates metabolism metabolic promoted the propofol, of not but Sevoflurane, MPC1, cellular GLUT1, group. of those expressions HIF-1 upregulated inhibited with p-Erk1/2, propofol associated GLUD1, anaesthetic be viability, could intravenous cell observations contrast, phenotypic cancer These ovarian In activities. enhanced invasion. sevoflurane and anaesthetic migration, inhalational proliferation, that suggested study current Our ( control propofol the by decreased Discussion than but group sevoflurane by propofol increased the both control, were in CXCR4 the administration. lower and than CXCL12 group was of sevoflurane marker expressions the the the in showed higher of ( was intensity (CXCR4) group was the 4 propofol (CXCL12) receptor and the 12 chemokine in motif ligand decreased C-X-C chemokine of but motif staining group C-X-C sevoflurane of the intensity in the increased expressions staining, CXCR4 immunofluorescent and to CXCL12 According on propofol 1.0 or sevoflurane S, of vs. Effects (NC control the to compared treatment p propofol (NC after sevoflurane decreased with significantly administered cells cancer after < .5 )( 6) = n 0.05, i 4F Fig α, ). XL2adCC4 n oneuae EFepeso ntesevoflurane the in expression PEDF downregulated and CXCR4, and CXCL12 GLUT1 vs 6 eei arpae Tnk ta. 00 n this and 2010) al., et (Tanaka macrophages in gene ,1.0 S, . ± 0.3 vs i 5A Fig 1.5 . bee ta. 08.Another 2018). al., et ¨ obbeler ± .I iia,tefluorescent the similar, In ). .,p 0.5, i 5B Fig < ± .5 ) but 6), = n 0.05, . s 0.4 vs. 0.3 .Teeresults These ). ± 0.3, via Posted on Authorea 25 Feb 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161425406.62861504/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. neteissvflrn rdsuae ritaeosaashtcpooo uigsreyadtesurvival the and surgery inhalational during with How- propofol anaesthetised limited. were anaesthetic be patients intravenous may cancer or cell study rectal current cultured desflurane, and our our or colonic of Secondly, sevoflurane breast, implications growth. studies, anaesthetics the and clinical Therefore, acti- some proliferation pathway human. in cell to signalling and ever, relevant for cellular be changes up survival not use signalling to example, may substrates for study due cellular that, energy development likely between more and very whereby relationship survival is vation it cell causal However, cancer the unknown. promotes remains Firstly, sevoflurane anaesthetics pathway, by signalling induced limitations. 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Erk1/2 propofol a that study, treatment. to current findings propofol the led our with In which found with uptake, was consistent effect glucose were opposite and an reports expression However, These GLUT1 2016). the Silva, increased was of & but decrease overexpression GLUT1 the a Diaz-Corrales, administration of that to (Calado, reported led sevoflurane expression which also study glucose, the after Another of the epithelium, 2016). uptake decreased of Silva, Sim˜ao, increased pigment & Alves, was the (Calado, retinal in PEDF expression resulted human PEDF that of In condition hypoxia level under treatment. expression increased propofol the after study, increased 2016). that membrane current cell al., cellular found et the from of was (Zhang roughness come it In surface manner study, also the glycerol dose-dependent earlier might that a of an cells acids in changes From HeLa fatty cycle decreased of the TCA and them. was ultrastructure and Thus, membrane into glycerol function the down The affected mitochondria 2006). broke propofol the treatment. phospholipids Liu, that propofol and Through (Y. evidence by degradation another group. cycle membrane disturbed were propofol TCA group or the the propofol inhibited in in the was in used increased acids were and fatty acids generated level and increased fatty is the and acetyl-CoA (Beauchamp, to glycerol contribute acids, acetone also group. of to may propofol levels which converted the 2017), The cells of reversibly Duan, media cancer & be ovarian the Cheng, can of cancer in Liu, ovarian acetone malignancy Isopropanol Liu, of of the Li, isopropanol. malignancy 2016; inhibited of Kim, the propofol & level enhanced while whichValento, malignancy, sevoflurane isopropanol, the diagnosis cancer that of cancer decreased with level lung study correlations and for the this some biomarker increased exhaled had of potential and isopropanol the findings a of cells in the as level increased with the regarded was consistent seemed been propofol isopropanol It was had and 2017). of it al., sevoflurane level and et between the patients, (Chien cancer that metabolites lung reported of of was change” breath It “mirror isopropanol. TCA another our the was with glutamine, in administration consistent used and was be which glucose 2018), can Except al., that et acids (Pasini amino arginine exposure, media and With propofol asparagine in promoted. to findings. after as glutamine then such cycle cycle was of accumulated, TCA glutaminolysis TCA were concentration the and the cycle decreased increased of of likely function The was activity disturbed progression. glutamine the the the of and utilisation administration, enhance survival the sevoflurane might cancer of that after which suggested of effects that upregulated, inhibitory demands demonstrated unlike were the data that expressions meet ischaemic Our reported myocardial GLUD1 2020). also a and Smul, in was chain MPC1 & It respiratory Stumpner, 2018). mitochondrial the (Lotz, al., chain, of et model function respiratory (Berndt the mitochondrial preserved cycle the sevoflurane disturb TCA propofol, might to propofol related showed was studies which other from Evidence 2020). Han, PEDF α, XL2adCC4epesos hl rpfldwrgltdteemlclrentities. molecular these downregulated propofol while expressions, CXCR4 and CXCL12 eei iewsrltdt h euto fguoeutk n erae xrsino GLUT1 of expression decreased and uptake glucose of reduction the to related was mice in gene CXCL12 7 and CXCR4 Gl ta. 00 u ta. 2020). al., et Xue 2020; al., et (Gola α soeepesd which overexpressed, is β- xdto ffatty of oxidation α Posted on Authorea 25 Feb 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161425406.62861504/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. nud . egud . nrasn . ie,C,Eln,A,&Brkit .(04.Tecoc of choice The (2014). L. analysis. Bergkvist, retrospective & a A., surgery: Enlund, cancer breast C., from on Cicek, outcome sevoflurane K., propofol–and of Andreasson, or Effects A., anaesthetic–sevoflurane (2013). Berglund, J. M., D. Buggy, Enlund, & vitro. P., in Doran, function D., cell Murray, cancer B., McHugh, P., Ecimovic, og . a,G,Yn . in . i . eg .(09.Fbiaino evrto otdgold coated resveratrol diabetic of induced Fabrication streptozotocin (2019). in G. retinopathy Peng, diabetic & on F., effect Li, their C., of rats. Qian, investigation P., Yan, and G., nanoparticles Wan, metabonomics. robust NMR Y., as 1H Dong, in normalization Application quotient mixtures. Probabilistic biological (2006). complex 78 H. of R. Senn, Chem, dilution A. for & Green, account G., to . Schlotterbeck, method . A., . Ross, B., F., Masisi, Dieterle, L., Alfarsi, cancer. W., breast K. in doi:10.1007/s10549-018-5060-z Cheng, expression 79-91. A., (GLUD1) M. dehydrogenase Aleskandarany, Glutamate in R., (2019). Bio-sniffer El-Ansari, isopropanol (2017). L., of K. M. Mitsubayashi, determination Craze, . for . biomarker. (S-ADH) volatile . potential T., dehydrogenase a Arakawa, as alcohol K., air Toma, secondary exhaled M., with Ye, Dia- M., biosensor) Ameliorates Tsujii, (gas-phase Expression T., Suzuki, PEDF J., pEPito-driven P. (2016). Chien, A. G. Silva, Hallmarks. impairment & Retinopathy the F., to betic Diaz-Corrales, contributes M., activity GLUT1 S. (2016). Calado, RPE. A. the G. Silva, by & secretion Sim˜ao, S., PEDF S., of L. Alves, M., S. countries. statistics Calado, 185 cancer in Global cancers (2018). 36 A. 68 for Jemal, worldwide Clin, & mortality A., and J L. incidence Torre, in of L., chain estimates R. GLOBOCAN respiratory Siegel, 2018: the I., of Soerjomataram, J., II Ferlay, F., complex Bray, slices. of hippocampal inhibition rat the of for evidence CA3 man- propofol: area and anesthetic recognition the prompt of neurotoxicity ingestion: alcohol R Toxic N., Berndt, (2016). [digest]. department J. emergency Kim, the & in M., agement Valento, settings. A., clinical G. in Beauchamp, propofol, further and study sevoflurane to of subjected properties anti-tumour is References and these pro- of value the indicate translational study The present respectively. the in found lations HIF-1 Furthermore, pathway, treatment. inhibition Erk1/2 propofol PEDF upregulated after sevoflurane identified through GLUT1 was expression propofol, PEDF upregulated decreased to of a The contrast expression in increased in resulted features. an exposure metabolic by opposite, sevoflurane different In regulations after uptake PEDF. to These glucose of led increased molecules. of turn, cells these in expressions cancer and, of ovarian GLUD1 expression expressions on and the propofol MPC1, downregulated or GLUT1, propofol sevoflurane upregulated while sevoflurane cells, cancer that evaluateovarian demonstrated to study needed current be may The urgently propofol are outcomes. while studies surgical patients, retrospective clinical the cancer and optimise Therefore, for Conclusions here to factor reported patients surgery. risk one cancer their a for the for be anaesthesia regimens including patients might anaesthesia inhalational data sevoflurane cancer with Laboratory that to those to 2018). beneficial point than al., all higher et data Wu significantly clinical 2014; were al., patients et anaesthetised (Enlund propofol of rate htce htbo ,195 B, Photobiol Photochem J 1) 2149.doi:10.1021/ac051632c 4281-4290. 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S. ¨ astner, rnsCl il 27 Biol, Cell Trends aue 496 Nature, α/ D-/XR sig- SDF-1/CXCR4 4,2767-2774. (4), 12,172-182. (1-2), x o Med Mol Exp 74) 101- (7443), 2,70-76. (2), Vaccines (9), Lab Posted on Authorea 25 Feb 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161425406.62861504/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. vra acrclswr diitrdwt ei n¨v oto) .%svflrn,o 4 or sevoflurane, HIF-1 and 2.5% ΠΕΔΦ/Ερκ/ΗΙΦ-1α (na¨ıve (A) control), PEDF media ον of with expressions προποφολ administered The were ανδ cells σεvοφλυρανε cancer Ovarian οφ ςελλς. arginine; ςανςερ εφφεςτς Arg: οvαριαν οπποσιτε acetone; ιν Τηε Acn: πατηωαψ succinate; leucine; 4. Suc: Leu: acids; Φιγ valine; fatty Val: FA: isopropanol; asparagine; IPA: Asn: alanine; isoleucine. Ala: lac- glycerol; Ile: Lac: acetate; Gro: glucose; Ace: ethanol; Glc: glutamine; component Eth: analysis; principal Gln: structures-discriminant PCA: pyruvate; group; latent Pyr: propofol to tate; P: projection group; orthogonal sevoflurane S: OPLS-DA: (r group; analysis; values control NC coefficient vehicle (B: VC: correlation group; plots NC the control scores indicated (C: OPLS-DA bar plots The colour loadings The t[2]). and and P) (t[1] components . principal two for by collected modelled was cells SKOV3 1 cancer sevoflu- 2.5% ovarian control), of (vehicle 4 intralipid (na¨ıve using control), media or cells with rane cancer administered were ovarian cells propofol-treated cancer Ovarian or sevoflurane- of study metabolomics The 1 3. dehydrogenase glutamate Fig GLUD1: 1; variance. carrier of pyruvate analysis mitochondrial ANOVA: MPC1: 1; 1; transporter glucose GLUT1: h aawsaaye ihoewyAOAadDnetmlicmaio et(-)adwspresented was 50 GAPDH. and protein bar: (D-F) housekeeping Scale test by na¨ıve multi-comparison control. normalised versus Dunnett was and analysed ANOVA analysis also one-way mean blot was with as Western GLUD1 analysed of in was level these bands data of expression the levels The the and of expression and intensity The MPC1, analysis The blot staining. Western GLUT1, immunofluorescent (C). with with validated of detected were were markers (B) expressions 4 two MPC1 or and the sevoflurane, (A) 2.5% (na¨ıve GLUT1 on control), media of to propofol exposed were and cells SKOV3 sevoflurane cells. cancer of ovarian effects in data GLUD1 The The (D G). 2. assay and Fig healing (F assay wound and Transwell 100 with (B with bar: closure cells cells Scale na¨ıve invasive gap control. positive versus identifying mean calculating Ki-67 by as by identifying evaluated expressed evaluated by was was was invasion evaluated cells The was SKOV3 E). cells and of cancer migration ovarian The of C). proliferation cell The (A). vra acr(KV)clswr diitrdwt uecluemda(aıecnrl,25 sevoflurane, after 2.5% (na¨ıve cells control), media cancer culture pure ovarian deficiency with 4 of MPC1 administered or were invasion cells and (SKOV3) (2019). cancer migration, C. Ovarian proliferation, Xu, administration. viability, propofol cell . or The sevoflurane . 1. Fig . Y., Yuan, Legends H., Figure Wu, S., pathway. STAT3 Wang, the A., through doi:10.1038/s41419-019-1324-8 progression Zhang, adenocarcinoma Q., lung accelerates Chen, Carcinoma. H., Death Cell Zou, and Recurrence Squamous Early Esophageal (2011). Y.-T. With Chen, 91 Patients & Surgery, L.-Q., in Chen, X.-Z., Esophagectomy Chen, Y.-F., After Zhao, Y., Hu, Z.-J., Zhu, doi:10.1016/j.aat.2014.05.008 -M pcr fmdawsson() R (A). shown was media of spectra H-NMR -M spectroscopy. H-NMR μ /Lpooo.Tecl iblt foaincne el a vlae ihcl onigkt8assay kit-8 counting cell with evaluated was cells cancer ovarian of viability cell The propofol. g/mL ± μ tnaddvainaddt lt( ) *p 6). = (n plot dots and deviation standard /Lpooo o or ls2 or eoeytm.Atrtetet h utr media culture the treatment, After time. recovery hours 24 plus hours 2 for propofol g/mL 5,10-58 doi:10.1016/j.athoracsur.2011.01.007 1502-1508. (5), ± tnaddvainaddt lt( ) *p 6). = (n plot dots and deviation standard vs ;E VC E: S; . μ μ .N:n¨v oto ru;S eouaegop :pooo group; propofol P: group; sevoflurane S: group; na¨ıve control NC: m. .N,n¨v oto ru;S eouaegop ,pooo group. propofol P, group; sevoflurane S, group; na¨ıve control NC, m. α ( Β eedtce ihimnfloecne h xrsinlevels expression The immunofluorescence. with detected were ) 2 ersne h rcino ainei the in variance of fraction the represented X vs )wr eie from derived were P) . 1 -M pcrsoyeprmn.PAsoe ltof plot scores PCA experiment. spectroscopy H-NMR 11 < .5 **p 0.05, 2 ob ihi e n o nbu.N:na¨ıve NC: blue. in low and red in high be to ) < < .1 ***p 0.01, 1 .5 **p 0.05, μ -M pcrldt n=10). = (n data spectral H-NMR elDahDs 10 Dis, Death Cell /Lpooo.Teexpressions The propofol. g/mL h naso Thoracic of Annals The < < .0,****p 0.001, .1 ****p 0.01, vs μ /Lpropofol. g/mL 1 ;D VC D: S; . -M data H-NMR 3,148-148. (3), < < 0.0001 0.0001 vs Posted on Authorea 25 Feb 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161425406.62861504/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. fbt akr.N:n¨v oto ru;S eouaegop :pooo ru;CC1:CXCmotif C-X-C expressions CXCL12: the group; 4. decreased propofol receptor propofol P: chemokine while motif group; increased C-X-C sevoflurane cells, detected CXCR4: S: exposure cancer were 12; group; ovarian Sevoflurane (B) na¨ıve ligand control CXCR4 in NC: chemokine and (blue). CXCR4 markers. (A) DAPI and both CXCL12 with CXCL12 of of overlaid of expressions and expressions The or (green) recovery. the 4 hours staining or sevoflurane sevoflurane, 24 immunofluorescent after 2.5% by (na¨ıvewith control), cells followed media and culture cancer hour pure ovarian to 2 in exposed were CXCR4 cells and SKOV3 CXCL12 of expressions exposure. The propofol 5. variance.Fig of HIF-1 analysis 2; ANOVA: and alpha; 1 factor-1 kinase hypoxia-inducible phospho-extracellular-signal-regulated multi-comparison p-Erk1/2: Dunnett factor; with epithelium-derived ANOVA pigment one-way 50 with bar: analysed Scale mean na¨ıve control. was as presented Data and (E). test Erk1/2 by normalised was HIF-1 HIF-1 and and PEDF Erk1/2, p-Erk1/2, PEDF, of α ad a omlsdb AD DadF.Wieteitniyo -r12band p-Erk1/2 of intensity the While F). and (D GAPDH by normalised was bands ± μ .N:n¨v oto ru;S eouaegop :pooo ru;PEDF: group; propofol P: group; sevoflurane S: group; na¨ıve control NC: m. tnaddvainaddt lt( ) *p 6). = (n plot dots and deviation standard α eeeautdwt etr ltaayi C.Teitniyof intensity The (C). analysis blot Western with evaluated were 12 < .5 ****p 0.05, μ /Lpooo for propofol g/mL < .01versus 0.0001 α: Posted on Authorea 25 Feb 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161425406.62861504/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 13 Posted on Authorea 25 Feb 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161425406.62861504/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 14 Posted on Authorea 25 Feb 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161425406.62861504/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 15 Posted on Authorea 25 Feb 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161425406.62861504/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 16 Posted on Authorea 25 Feb 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161425406.62861504/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. metabolic-and-signalling-mechanisms but-not-propofol-enhances-ovarian-cancer-cell-malignancy-through-regulating-cellular- Tables.pdf file Hosted vial at available https://authorea.com/users/398071/articles/510772-sevoflurane- 17