Novel Mechanisms for DHEA Action

Home , HHEX, Neurotrophin, NFATC2, Okadaic acid

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r a prough and others DHEA activation of receptors 56:3 R139–R155 Review

Novel mechanisms for DHEA action

Correspondence should be addressed Russell A Prough, Barbara J Clark and Carolyn M Klinge to C M Klinge Department of Biochemistry and Molecular Genetics, Center for Genetics and Molecular Medicine, Email University of Louisville School of Medicine, Louisville, KY, USA [email protected]

Abstract

Dehydroepiandrosterone (3β-hydroxy-5-androsten-17-one, DHEA), secreted by the Key Words adrenal cortex, gastrointestinal tract, gonads, and brain, and its sulfated metabolite ff DHEA DHEA-S are the most abundant endogeneous circulating steroid hormones. DHEA ff DHEA-S actions are classically associated with age-related changes in cardiovascular tissues, ff nuclear receptors female fertility, metabolism, and neuronal/CNS functions. Early work on DHEA action ff G-protein-coupled focused on the metabolism to more potent sex hormones, testosterone and estradiol, receptors and the subsequent effect on the activation of the androgen and estrogen steroid receptors. However, it is now clear that DHEA and DHEA-S act directly as ligands for many hepatic nuclear receptors and G-protein-coupled receptors. In addition, it can function to mediate acute cell signaling pathways. This review summarizes the molecular mechanisms by which DHEA acts in cells and animal models with a focus on the ‘novel’ Journal of Molecular and physiological modes of DHEA action. Endocrinology (2016) 56, R139–R155

Introduction DHEA synthesis and metabolism overview

Journal of Molecular Endocrinology Metabolism of dehydroepiandrosterone (3β-hydroxy-5- DHEA synthesis mainly occurs in the adrenal zona androstene-17-one, DHEA) and its 3β-sulfated metabolite reticularis: the inner zone of the adrenal cortex DHEA-S provides ~50% of androgens in men and ~75% (Parker Jr 1999; Rainey & Nakamura 2008). All steroid of estrogens in premenopausal women (Maggio et al. hormones are derived from cholesterol with the first 2015). Circulating levels of DHEA/DHEA-S decline enzymatic reaction occurring in the mitochondria. with age (Labrie 2010), and this age-related decline in The steroidogenic enzymes and pathway for DHEA DHEA, DHEA-S, and other metabolites is associated synthesis in the adrenal have been well characterized and with changes in cardiovascular tissues (reviewed in reviewed in detail and will only be briefly summarized Mannic et al. 2015, Ohlsson et al. 2015), female fertility herein (reviewed in Miller & Auchus 2011). Cholesterol (Labrie 2015a, Tartagni et al. 2015), and metabolism, transport across the mitochondrial membranes requires and neuronal/CNS functions (reviewed in Maninger the action of the steroidogenic acute regulatory protein et al. 2009, Traish et al. 2011, Maggio et al. 2015). In (STAR) (Clark & Stocco 1997). The cytochrome P450 addition to providing precursors for sex steroids, (CYP) side-chain cleavage enzyme (CYP11A1 encoded DHEA binds directly to steroid hormone and nuclear by the CYP11A1 gene) is located in the inner membrane receptors (NRs), activating various membrane receptors of the mitochondria and converts cholesterol to and inhibiting voltage-gated T-type Ca2+ channels. pregnenolone. CYP11A1 is part of an electron transport This review summarizes the established mechanisms complex that includes the flavin adenine dinucleotide by which DHEA activates its biological effects in (FAD) FAD-containing adrenodoxin reductase and cells, including receptors and intracellular signaling iron–sulfur protein, adrenodoxin, that transfer reducing pathways. equivalents from NADPH to CYP11A1 for two sequential

http://jme.endocrinology-journals.org © 2016 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-16-0013 Printed in Great Britain Downloaded from Bioscientifica.com at 10/03/2021 12:09:15AM via free access

10.1530/JME-16-0013 Journal of Molecular Endocrinology family thatcatalyzesboththeoxidationof3 HSD3B2 isamemberoftheshort-chaindehydrogenase androstenedione (4-androstene-3 dehydrogenase/∆5– C4–C5 positionwithintheAringby3 C5 andC6oftheBringthatcanbeisomerizedto adrenal androgens.DHEAhasadoublebondbetween group atC17,whichisthecharacteristicfeatureof generate DHEA.TheactionofCYP17A1 generates aketo of theC17–C20bond17 generate 17 reactions: hydroxylationofpregnenoloneatC17to (reviewed in gene) thatdonateselectronfromNADPHtotheCYP17A1 NADPH-CYP oxidoreductase(POR,encodedbythe The enzymeispartofaminielectrontransportchainwith attached viaanaminoterminalstopanchorsequence. integral membraneproteinoftheendoplasmicreticulum CYP17A1 17 pregnenolone isconvertedtoDHEAbytheactionofCYP pregnenolone followed by cleavage of the C22–C20 bond to form hydroxylation reactionsatC22andC20ofcholesterol small intestine,colon,spleen,prostate, andtestis.Thispathwayisreviewedin AR. AKR1C4isliverspecific,whereas AKR1C3isexpressedinmanytissues,includingtheadrenal,brain,kidney, liver, lungmammarygland, placenta, Selected aspectsofDHEAmetabolism. ThismodelshowssomeofthepathwaysandenzymesbywhichDHEA ismetabolizedtosteroidsthatbindERand Figure 1 DOI: 10.1530/JME-16-0013 http://jme.endocrinology-journals.org Review α -hydroxylase/17,20-lyase (CYP17A1encodedbythe gene)(reviewedin α -hydroxypregnenolone, followedbycleavage Miller 2005) (Mast ∆ etal. 4 isomerase( 2011). . CYP17A1hastwoenzymatic Auchus 2004 α -hydroxypregnenolone to r Inthezonareticularis,

,17 prough HSD3B2 β -dione, Adione). β ). CYP17A1isan -hydroxysteroid andothers Printed inGreatBritain ) forming β -hydroxyl POR

Labrie C17-keto steroidstoC17-hydroxysteroids oxidation reactionsatC17forreversibleconversionof aldo–keto reductasefamilythatcatalyzesreduction– 3 encoded bythe by 17 Alternatively, theC17ketogroupofDHEAcanbereduced in anNAD double bondfromtheC5–C6toC4–C5position group tothe3-ketoandisomerizationof 2008) hormonally regulated(reviewedin DHEA andDHEA-Ssynthesisaredevelopmentally 3 hormone modification whichincreasesthesolubilityofsteroid steroids through sulfation of free hydroxyl groups, a of NRsasdescribedlater. Sulfotransferaseenzymesmodify Both AdioneandAdiolhavebeenreportedtobeactivators (Labrie adrenal DHEA-Sconversiontoestrogensinfattissue women inwhomthemajorsource ofestradiolisfrom biological functionofadiposeinpostmenopausal the actionofsteroidsulfatase,andthisisanimportant DHEA activationofreceptors β β Published byBioscientifica Ltd. ,17 ʹ -hydroxyl grouptogenerateDHEAsulfate(DHEA-S). etal. β . RegenerationofactiveDHEAoccursintissuesvia β -diol (Adiol) -hydroxysteroid dehydrogenasetype5(17BHSD5, etal. 2001 (Mueller + 2007) -dependent reaction ; Labrie AKR1C3 . et al. et al ( Fig. 1 . 2005;Labrie2015 2015) gene)togenerate5-androstene- Downloaded fromBioscientifica.com at10/03/202112:09:15AM ) . 17BHSD5isamemberofthe . DHEA is modified atthe (Persson Rainey &Nakamura a,b 56 . : 3 (Jez etal. etal. 2009) 1997) R140 via freeaccess . .

Journal of Molecular Endocrinology and increases increases STAR tothemitochondria forcholesteroldelivery kinase A (PKA)-dependent signaling. PKA signaling rapidly adrenocortical cellsandactivatescAMP-dependentprotein (PM) G-protein-coupledreceptors(GPCRs)locatedon (ACTH). ACTHbindstomelanocortin-2plasmamembrane synthesize andsecreteadrenocorticotropinhormone to the hypothalamusstimulatesanteriorpituitary axis. Corticotropin-releasinghormonereleasedfrom signaling cascade of the hypothalamic–pituitary–adrenal the gonads,liver, adrenals,andperipheraltissues testosterone and5-dihydrotestosterone(DHT),occursin circadian patternofACTH secretion adults, DHEAlevelspeakinthemorning,following expression tomaintainanincreaseinsteroidoutput.In CYP2C9, BMF these genes: of DHEA-Sareregulated~60%bygenotypesatlocinear genome-wide association studies indicate that serum levels et al. and DHEA-S in women and men aged 60–80 to thelowernanomolarandmicromolarrangesforDHEA 1–10 DHEA-S levelsareanorderofmagnitudehigherinthe 25 and pre-postmenopausalwomenrangefrom10to to prepubertallevels.DHEAlevelsinplasmaadultmen aroundage20followedbyage-dependentdecline observed reticularis in humans, and peak DHEA/DHEA-S levelsare coincident with the differentiationof adrenal zona 1 2 AR Table 1 DHEA-S, whereasinpostmenopausalwomen,over90% of testosterone isderivedfromperipheralmetabolism of 2005) to maintainDHTlevelsintheprostate castration, adrenalandrogensaretheimportantprecursors in theabsenceoftestis-derivedtestosterone,such as fraction, lessthan5%ofthetotaltestosterone.However, DHEA tocirculating small testosterone representsavery In men with normal testis function, the contribution of

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Journal of Molecular Endocrinology activity inMCF-7breastcancercells activation ofARwasreportedtohaveantiestrogenic (Liu &Dillon2004,Liu intracellular MAPKsignalinginendothelialcells(ECs) possibility thatfitswithDHEAactivationofPM-associated andactivatesER phosphorylates action. One possibility is that DHEA may activate MAPK that cell-specific factors mitigate whether DHEA activates ER ER cells luciferase reporterassayintransientlytransfectedCOS-1 domain ofER DHEA (5 in ayeastreporterassay metabolism ofDHEAtoestrogens.alsoactivatedER However, inthesestudies,theauthorsdidnotruleout metabolizing enzymesare regulated bysterolssuchas transcription of androstane receptor(CAR), andPXR,thatregulatethe A numberofthehepatic NRs,PPAR DHEA activation ofPPARs in DHEA-S, asligandsforARisdifficulttodiscern(reviewed androgens intheprostate,preciseactivityofDHEA, or in both receptorsareexpressed,includingprostate(reviewed ER et al. AR H874Yinprostatecancercellsthanwild-type DHEA showedhighertranscriptionalactivationofmutant antiestrogen 4-hydroxytamoxifen manner, ascertainedbyinhibitioncotreatmentwiththe the ERE-drivenluciferaseactivityinanER-dependent endometrial cancercells,DHEA(1 nonresponsive subline)breastcancercellsandIshikawa to E2intheGT1-7cells.InMCF-7andMCF-7SH(anestrogen (Bruder extent as10 in GT1-7 mouse hypothalamic neuronal cells to a similar response element(ERE)-drivenluciferasereporterassay DHEA (1 DHEA activation ofsteroid receptors (Kuiper both ER ~5 DOI: 10.1530/JME-16-0013 http://jme.endocrinology-journals.org Review

α β Arnold 2009 nM Arnold & Blackman 2005 by a mechanism other than direct binding and/or that byamechanismotherthandirectbindingand/orthat predominatesoverARactivationintissueswhich DHEA bindsARwith1–2 (Chen 1997) (Michael Miller etal. etal. α

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which are also transcriptionally regulated by T dehydrogenase ( malic enzymeandmitochondrial sn-glycerol-3-phosphate induce transcriptionoflipid metabolismgenessuchas by thyroidhormone(T CYP4A wasatranscriptionalprocess. These studiesalsodemonstratedthatDHEAinduction of E proliferation thanDHEAitself of CYP4Aandanumbermarkersperoxisome agent, thatis,requiredatlowerdosesforinduction and Adioldemonstratedthatwasabetterinducing DHEA inductionofratCYP4A using isolated rat hepatocytes hepatocytes Adiol activatedperoxisomeproliferationinculturedrat proliferation werealsoelevated 16.9-fold. Othermarkerenzymesforperoxisomal was laurate the livermicrosomes,majorCYPactivityinduced daily for4 approximately 1.8–2.0-foldatthe50 and its flavoproteinoxidoreductasewere increased diet containing0.45%DHEA,thelevelsoftotalCYP genes induction ofthehepaticandrenal effect ofDHEAfeedinginratswithhepatomegalyand 1985) 1982) obesity are decreasesintheincidenceofgeneticallydisposed other beneficialeffectsofDHEAfeedinginrodents tumors infemalemice appearance ofvirallyinduced,spontaneousbreast (Pashko 7,12-dimethylbenzanthracene andphorbolesters 1981) of 7,12-dimethyl-benzanthracene (Nyce colon cancercausedby1,2-dimethylhydrazineexposure incidence ofchemicallyinducedcancers,forexample, of leanbodymass,improvedcoatcolor, anddecreased reported in rodent studies, including the maintenance ad libitum studies inwhichrodentswerefeddietscontainingDHEA these NRscamefromaseriesofexperimentalpathology (Webb DHEA, asinitiallyreviewedbyWebb andcoworkers DHEA activationofreceptors 2 Published byBioscientifica Ltd. treatmenthadlittleornoeffectonthesemarkers. We alsowereinterestedinregulationoftheseprocesses In 1993,Sakumaandcoworkersreportedthat , andskinpapillomacausedbypaintingwith . Our early work with DHEA led us to study the , andsystemiclupuserythematosus et al. etal. (Wu (Yen et al. . ManybeneficialeffectsofDHEAhavebeen

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Journal of Molecular Endocrinology (WY14643, asyntheticPPAR induction ofCYP4AexpressionbyWyeth14643 K induced theexpressionof 7 et al and its metabolites to induce CYP4A1 expression rathepatocytestotestthe abilityofDHEAused primary more than40-fold known peroxisomeproliferator, increasedtheactivity luciferase reporteractivity, whereasnafenopin, a DHEA metabolitestestedincreasedPPAR to oursurprise,neitherDHEA,DHEA-S,noranyofthe gene inculturedhumanhepatomaHepG2cells.Much of atransfectedPPAR various DHEA metabolites to induce the expression our firststudiesweredesignedtotesttheability of 2013) expression. other receptorsmaybeinvolvedinDHEAinducedgene NADPH:CYP oxidoreductasedonot,suggestingthat their 5’-flanking regions of their genes, but others like putative peroxisomeproliferatorresponsiveelementsin of thegenesinducedbyDHEAfeedingwerenotedtohave of DHEA were most potent in regulating receptors. Many transfection assaystomoreeasilytestwhichderivatives receptors involvedinDHEAactionusingtransient hypothyroid rats. most suppressedbythephysiologicaldosesofT of T results inbloodlevelsofthehormonenear doses ofT hypothyroid ratstreatedwith10 transcriptional regulationwasstrikinglysuppressedin high T expresses CYP4A2,wasalsosuppressedmorethan95%at protein levels. CYP4A2 transcript in kidney, which only CYP4A2, andCYP4A3over70%atthemRNA weight), suppressedDHEAinductionofhepaticCYP4A1, T supraphysiological acyl-CoA oxidaseactivity( measured byNADPH:CYPoxidoreductaseandfatty affect DHEA-dependentperoxisomeproliferationas subsequently showedthattreatingratswithT was suppressedinliversofhypothyroidanimals.We (1991) enzyme byDHEA( T α 3 http://jme.endocrinology-journals.org DOI: 10.1530/JME-16-0013 m Review wasshowntoberequiredforinductionofmalic -hydroxy-DHEA, 7-oxo-DHEA, and7-oxo-Adiol) for7-oxo-DHEAthis inductionwas~7 Knockout of In lightofthesestudies,wesoughttodefinethe 3 . 2006) seenineuthyroidrats.Interestingly, CYP4A2was ) andDHEA-S notedthatDHEAinductionoftheseenzymes 3 doses.We subsequentlydemonstratedthatthis 3 dailyfor4 . DHEA and its metabolites (Adiol, DHEA-S, Ppar (Webb in vivo Song 3

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Wy14643 decreasedthe levelsofPPAR cultured rat hepatocytes, DHEA, nafenopin, and primary PPAR of by over 60%, supporting that dephosphorylation to alanineincreasedPPAR demonstrated thatthemutationofserineresidues region ofPPAR of thesethreeserineresidues(6,12,21)intheN-terminal (Tamasi PPAR suggesting thattheperoxisome-proliferatingagentsinduce ofserine6,12,and21, decreased thephosphorylation mRNA andproteinbytwo-tofour-foldconcomitantly (EMS) andincreased activity and activation of liver CAR for 15 mice fedDHEA-orDHEA-S-containing food(0.4%w/v ligands as by other compounds that possibly act as direct CAR thatisupregulatedbyphenobarbital aswell gene battery regulated throughCARactivation,beingamemberofthe PPREs in their 5 and proteinlevelsinratliver, geneswithnoobservable NADPH:CYP oxidoreductase(POR)andCYP3A23mRNA ofDHEA stimulationof came fromtheobservations The suspicionthatotherNRsareactivatedbyDHEA DHE rat hepatocytesandHepG2cells PPAR protein kinasesregulatethetranscriptionalactivityof DHEA transcriptionally regulates to controllevelsby24 relative tonafenopin,butmRNAlevelsdecreasedrapidly DHEA causedaneigth-foldincreasein rathepatocytesdemonstratedthat mRNA levelsinprimary Measurement of hepatocytes. stimulated byDHEAtreatmentofprimary Okadaic acidalsobluntedPPAR PPAR of PP2A,amulti-subunitproteinphosphatase,causes whereasOkadaicacid,apotentinhibitor phosphorylation, HepG2 cells. rathepatocytes,butnotthat ispresentintheprimary transcription factor or modulator in addition to PPAR DHEA anditsmetaboliteinHepG2cellsmustrequirea These resultsdemonstratethatinductionofCYP4A1by DHEA activationofreceptors Published byBioscientifica Ltd. DHEA andWY14643inducedthelevelsofPPAR α α α α A activation ofCAR

stimulatesitsactivity status levelsanddecreaseitsoverallphosphorylation through direct protein phosphorylation in primary in primary through direct protein phosphorylation atthoseresidues. tobecomefullyphosphorylated days) hadhepatomegaly, peroxisomeproliferation, etal. (Kobayashi in vitro 2008) α inanelectrophoreticmobility shiftassay ʹ -flanking regions (data not shown). POR is affectsPPAR PPP2CA et al. . We examinedifthephosphorylation Cyp2b10

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Journal of Molecular Endocrinology present through complex therefore, CARissequestered in a cytoplasmicprotein and, ERK thatkeepthreonine38 ofCARphosphorylated 2013) EGF receptor (EGFR) in the cell membrane blocks thebindingofepidermalgrowthfactor(EGF) to ligand-independent mechanism,inwhichphenobarbital coworkers describedtheactivationofCARthrougha et al. activate thegeneexpressionofitstargets signal andCARtranslocationtothenucleus to CAR, resultinginexposureofCAR’s nuclearlocalization of is disruptedbyPP2A-dependentdephosphorylation CAR islocalizedinacytoplasmicproteincomplexthat to thenucleus by mediatingthetranslocationofCARfromcytosol phosphatase 2A(PP2A)isrequiredforCARactivation PP2A, Negishiandcoworkershaveshownthatprotein threonine 38 ofCARat nuclei, accompaniedbydephosphorylation subcellular localizationofCARfromthecytoplasmto direct ligandforCAR),DHEAcausedthechangein or 3,3 antagonist, androstanol.Finally, likephenobarbital This induction was blunted by the addition of the CAR alone, butnotwith7 CYP2B6 (Kohalmy CAR isactivatedtoincreaseitstranscriptionalactivity todocumentthat Urs MeyerandKatalinMonostory DHEA activatesCAR after DHEAfeeding,leavingopenthequestionofhow increased nuclear localization of RXR and not CAR (Fujita DOI: 10.1530/JME-16-0013 http://jme.endocrinology-journals.org Review In amannersimilartoourworkonPPAR 2008,Mutoh . EGFRmodulatestheactivation ofSRCkinaseand et al. mRNAwasinducedupontreatmentwithDHEA ʹ ,5,5 etal. (Kobayashi ʹ -tetrachloro-1,4-bis(pyridyloxy)benzene (a 2002) (Kohalmy (Kobayashi 2007) de novo . However, this study showed only etal. et al. β . Therefore,wecollaborated with . In primary humanhepatocytes, . Inprimary α etal. -hydroxy-DHEA or7-oxo-DHEA. synthesisdoesthatcomplex 2009) etal. 2015) 2007) r 2015) . Recently, Mutohand

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but notforthehumanreceptor 16 rifampicin butnotthemurine receptor. Pregnenolone each receptor;thehuman receptoris activated by to havedifferences,inwhich theligandactivates 2002). localization. We suggest a role for PP2A that appears to cytoplasmic protein complex releasing CAR for nuclear of CAR,directligandbindingtoCARalsodisruptsthe nuclear transport allowing dissociate (afterCARdephosphorylation) activity atlowmicromolarconcentrations of DHEA haveno effect in stimulating PXRE-luciferase (Ripp responsive element(PXRE)fromtherat cells, usingavectorcontainingtwocopiesofthePXR and AdioneactivatePXRinluciferaseassaysHepG2 Other experimentsdemonstratedthatDHEA,Adiol, andRAPrough,unpublishedobservations). (S J Webb P4503A11inductionupon DHEAfeedingnot observe null mice specific for two-fold increaseinthe enzymatic activityandmRNA to detecttheinductionof 2002) its metabolitesmayactasaligandofPXR a pregnanederivative,itwaslikelythatDHEAand in the livers of rats fed DHEA and, because DHEA is et al. PXR bindsanumberofpregnane-relatedsteroids DHEA activation ofPXR stimulated byDHEAtoactivateCAR we speculatebasedonourresearch citedabovemayalso be commonforbothPPAR DHEA activationofreceptors Published byBioscientifica Ltd. α -carbonitrile isagoodligand forthemousereceptor, 2013) etal. . Using HumanandmurinePXRshavebeenshown (Ripp 2002) . We the induction of P4503A23 observed Cyp3a11 Ppar etal. . However, other oxidizedmetabolites α ( experimental evidence). dashed arrow, speculationbasedon CAR activation.(Solidarrows,establishedfacts; that appearstobecommonforbothPPAR et al nuclear translocation complex todephosphorylateandincreaseCAR stimulating PP2ArecruitmenttotheCAR:HSP90 Phenobarbital wasreportedtoactivateCARby PPAR Possible mechanismbywhichDHEAactivates Figure 2 stimulates CARnucleartranslocation transcription which mayenhanceligand-activated induces PP2AthatdephosphorylatesPPAR Mutoh Fig. 2 -null micefedDHEA,wewereunable . 2007) inbothwild-typeandPPAR α 2002) independentofdirectbinding. et al ) Downloaded fromBioscientifica.com at10/03/202112:09:15AM . InadditiontoPP2Aactivation ; hence,wesuggestaroleforPP2A α . 2013;Kobayashi andCARactivation,which (Tamasi . In Cyp4a1 Pxr (Kliewer et al (Yoshinari -null mice,wedid ( , buttherewasa 56 Fig. 2 . 2008) : 3 et al Cyp3a23 etal. ) etal. . . DHEA (Ripp (Ripp . 2015) (Kohalmy 2003; 1998) R144 etal. etal. . DHEA (Chai gene α α , and via freeaccess α - .

Journal of Molecular Endocrinology EGFR, maybeapossibility mediated byothermembranereceptors,forexample, needed onDHEAactivationofMR,DHEA-MRcrosstalk MR authors toconcludethatDHEAisnotadirectligandof in transiently transfected CHO-K1 cells, leading the did notactivatetheMR-luciferasereporteractivity MR antagonist eplerenone (10 transfection withsiRNAdirectedagainstorbythe Both ERK1/2andFOXO1activationwereblockedby andnuclearlocalizationinratVSMCs.phosphorylation the activation of ERK1/2 and increased FOXO1 2011) vascular smoothmusclecells(VSMCs) human skin fibroblasts, and either human or rat aortic in human umbilical vein endothelial cells (HUVECs), receptor (MR)isrequiredforDHEA-mediatedsignaling One study has indicated that the mineralocorticoid receptor DHEA activation ofmineralocorticoid sites ofthehumanandmousePXR results furtherdemonstratethedifferencesinactive activator thanDHEAandAdioneformurinePXR.These (Ripp upon theirconcentrationdependenceofactivation as DHEAorAdioneinactivatinghumanPXR,based For humanPXR,Adiolisnotagoodligandactivator differences betweenthehumanandmousereceptors. similarspeciesFor DHEAmetabolites,weobserved discussed inthefollowing section. these furtheroxidationproducts ofDHEAaswillbe et al. enzyme 11 metabolites ofDHEAarerapidly interconverted by the steroid hormoneNRs.Inaddition,thehydroxylated might expecttheactivationofgenesregulatedby these sterolsmaybeaccumulatedintheliver, one suggest thatunderadversepathologicalstatesinwhich for the concentration for circulating DHEA-S. We required fortheactivationapproachedthatobserved CAR, andPXRthanforERs activation arehigher(5–10 Although theeffectiveconcentrationsfor50% that are activated by foreign chemicals Conclusion aboutDHEAactivation ofNRs http://jme.endocrinology-journals.org DOI: 10.1530/JME-16-0013 Review (Lindschau 2003)

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- - NTR - References Niro Bonnet Shihan Mizota Liu &Dillon(2002,2004) Laurine Liang Svob Strac Lazaridis Rybczynska Chevalier Monnet Teng et al (2013), Pediaditakis Anagnostopoulou Gravanis Moriguchi (2004) (1998), Suzuki Compagnone &Mellon et al 56 et al et al . (2015) et al : et al et al 3 et al et al . (2012) et al . (2015) et al . (2015) et al et al . (2013) et al . (2005) . (2009) etal. . (2003) . (1995), . (2011), . (2012) . (2012) . (2012), . (2009), et al (2013) R146 et al . via freeaccess . Journal of Molecular Endocrinology MAPK (pERK1/2) activation, preventing degradation of 1 response ofrataorticVSMCstoAngiotensin2(ANG2, DHEA (100 DHEA’s inhibitionofSTAT3 activation.Morerecently, et al. that is, SRC/STAT3 activation and decreased STAT3 target genes, arterial hypertension,DHEA(100 cells isolatedfrompatientswithidiopathicpulmonary smoothmuscle artery conjugated DHEA.Inpulmonary and GSK-3 2009) both ER the activationofAKT/GSK3 smooth musclecell(hCASMC)proliferationbyblocking GPCR maybedifferentbetweencells. a commonGPCR-activatedsignalingpathway, evenifthe G activates ZIP9inGC-2cellshasnotyetbeenexamined. activation bound with theG-proteinGn IRT, iron-regulatedtransporter),whichdirectlyinteracts ZRT- andIRT-like proteins(ZRT, zinc-regulatedtransporter; et al. mitochondria (referredtoasmitochondrial-associated endoplasmicreticulummembrane(MAM) with referencestoeachreceptorincluded therein.Thesigma-1receptorplaysakeyroleinterfacebetween theendoplasmicreticulumand DHEA activationorinhibitionofPM receptors.ThismodelsummarizestheinteractionofDHEAwithPMreceptors asdescribedinthetextand Figure 3 http://jme.endocrinology-journals.org DOI: 10.1530/JME-16-0013 µM) byinhibitingROSproductionandp38MAPK α Review q/11 signalinginEC,BAEC,andGC2cells,suggesting 2016) DHEA was reported to inhibit human carotid artery DHEA wasreportedtoinhibithumancarotidartery These reportsshowthatDHEAandDHEA-Sactivate 2011) . ThisconclusionwasbasedontheinhibitionofAKT Ar α ). IP3RmodulatesCa PIM1 andAR,butthroughaPMGPCR inGC-2cellsleadingtoERK1/2,CREB,orATF-1 β (Shihan phosphorylation inhCASMCtreatedwithBSA- phosphorylation . However, nomechanismwasidentifiedfor µM) has suppressed the inflammatory µM) hassuppressedtheinflammatory , NFATC2 etal. 2015) , 2+ α homeostasis 11 andactsasamembrane- BMPR2 . WhetherDHEAorDHEA-S r β , and Survivin , andSurvivin

prough (Ruscher &Wieloch2015) andothers Printed inGreatBritain (Bonnet h) inhibited (Paulin et al. .

DHEA had a biphasic effect on miR-21 transcription with DHEA hadabiphasiceffectonmiR-21transcriptionwith of miR-21inHepG2cellspartviaGPERsignaling. reported thatDHEA(10 cell proliferation on itsabilitytoinhibitGPER-specificagonistG-1-induced GPR30/GPER inSKBR3andMCF-7breastcancercellsbased DHEA metabolite,7 2015, Prossnitz&Barton2014) adenylate cyclase,SRC,andEGFRsignaling activated, formsheterotrimericGproteinsthatstimulate PM receptorcoupledtoG G-protein ER(GPER;originallycalledGPR30) is an integral via DHEA’s rapid activation ofmiR-21expression effects wasnotidentified however, the mechanism by which DHEA achieved these cytoplasmic 1 MIR21 of DHEA. The initial rapid DHEA-induced increase in transcriptionaleffect cycloheximide, suggestingaprimary the transcriptionalinhibitoractinomycinD,butnot increase inpri-miR-21andmiR-21wasinhibitedby (Teng an increaseagainafter3 an initial peak at 1 DHEA activationofreceptors Published byBioscientifica Ltd. G-protein ER etal. (miR-21)transcriptionthatpeakedat1 2014,Teng (Cheng κ B andtherebyreducingNF (Niro etal. β h followed by a decrease and then -hydroxy-epiandrosterone, binds to -hydroxy-epiandrosterone, bindsto et al. etal. 2008;Bernard-Marissal Downloaded fromBioscientifica.com at10/03/202112:09:15AM nM) increased the transcription nM) increasedthetranscription α (Chen S in its inactive state and, when S initsinactivestateand,when h whichissustainedto12 2015) 2012) . It was suggested that the . Itwassuggestedthatthe etal. . The DHEA-induced . TheDHEA-induced 2014) . We have recently 56 : 3 etal. . κ (Gaudet B activation; 2015;Lewis h involved h involved R147 Table 2 etal. via freeaccess

h h

Journal of Molecular Endocrinology in pri-miR-21 transcription in DHEA-treated HepG2 cells was in pri-miR-21transcription DHEA-treatedHepG2cellswas rapid DHEAsignaling. our datasuggestedaneedfor intactlipidraftstructurefor transcript expressionwasinhibited thatDHEA-inducedpri-miR-21and maturemiR-21 observed removes cholesterolfromthePM signaling. Usingmethyl- 2015) into microdomainsatthePM to bepreorganized,sequestered,andcompartmentalized after 6 the longertermeffectofDHEAthatinvolveditsmetabolites for therapidactivationofGPERwith≤1 result helpedustodistinguishthemechanismsresponsible baseline controlafter6 induction ofER was abrogatedbysiGPER ER asapositivecontrol G-1, serving increased ER & Yin 2015) of theSRC/MEK1/2/AP1pathway ER proposed tomediate the membrane-initiatedeffects of E is aPM-associatedsplicevariantofER in HEK-293andCOS-7cells but hadnoeffectonc-FOSproteinlevelsinHepG2cells. (Chan MAPK-dependent mannerinPC-3prostatecancercells and G-1increasedc-JUNc-FOSexpressioninan SKBR3 (ER GPER activationby1 1998) anestablishedtargetofMAPK phosphorylation, factors increase theexpressionofdownstreamtranscription after DHEAtreatment.alsoincreasedER cells. ThepERK/ERKratioremainedelevated(>1)upto6 inaGPER-responsivemannerHepG2 phosphorylation protein levels.DHEAalsoincreasedERK1/2andc-SRC agonist G-1, increased GPER and ER transcription and BSA-conjugated DHEA-stimulated pri-miR-21 GPER-specific antagonistG-15attenuatedDHEA- of c-SRC,ERK1/2,andPI3K.We showedthatthe GPER, ER DOI: 10.1530/JME-16-0013 http://jme.endocrinology-journals.org Review α α 36 36 is a direct transcriptional target of GPER activation 36 isadirecttranscriptionaltargetofGPERactivation Altogether, ourdatasuggestthattheinitial rapidincrease Efficient signal transduction requires signaling molecules Efficient signaltransductionrequiressignalingmolecules Overexpression ofGPERinducedER . Therefore, we tested a role for caveolae in DHEA . Therefore,wetestedaroleforcaveolaeinDHEA . MAPKactivationby GPER hasbeen reported to mRNA expression after only 1 h, and this increase andthisincrease mRNAexpressionafteronly1 h,

h oftreatment et al. (Prossnitz &Maggiolini2009) α α 36, EGFR signaling, and G protein activation 2010). -) breast cancer cells ; asstatedpreviously, thatDHEA weobserved α 36 expression.Specifically, 10 (Teng α 36 was transient as levels returned to 36 wastransientaslevelsreturnedto We reportedthatDHEAincreasedc-JUN etal. (Teng

µM E

h of DHEA or G-1 treatment. This h ofDHEAorG-1treatment.This (Teng β 2015) etal. -cyclodextrin, an agent that -cyclodextrin, anagentthat 2 (Chaudhri increased c-FOS protein in increasedc-FOSproteinin (Martinez-Outschoorn (Kang et al. 2014) r . DHEA, such as GPER . DHEA,suchasGPER (Maggiolini

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IGF 1 receptor, PI3K, P38 MAPK, and ERK1/2 MAPK, but transcription mesenchymal stemcellsbyincreasingIGF1gene and stimulated osteoblast differentiation of human inhibited secretionofIL6,anosteolyticcytokine, women DHEA increasesthebonemineraldensityinmenand DHEA increases IGF-Ireceptor relevant levelinhumanserum cells treatedwith10 to themiR-21promoter. Importantly, theseresultsarefrom produced in these cells that activate ARand ER 6 second phaseofpri-miR-21transcription,examinedafter c-JUN protein expression andER SRC, EGFR,andMAPKsignalingresultinginincreased mediated byactivationofGPERandER that hasbeenassociatedwith theendoplasmicreticulum, Nusser 2005) potential whenactivated postsynaptic postsynaptic responses,that is, theinhibitory and bicarbonatechannelsthatpromotehyperpolarizing (GABA disorders & Szepetowski2015) have beenassociatedwithautismandepilepsy 2015) channels involvedinlearningandmemory and allostericeffectorstoregulatetransmembraneion heterotetrameric complexesthatbindneurotransmitters of a large family of glutamate receptors, which are large 2013) (Monnet &Maurice2006,Yadid associated withactivationorsuppressionofthesereceptors DHEA inalleviatingaspectrumonneurologicaldisorders supported theconceptforpotentialbeneficialeffects for rapid,nongenomicactionofDHEA/DHEA-Sand of thesereceptorsprovidedsomethefirstevidence (GABA d-aspartate (NMDA)receptor, modulators oftheneurotransmitterreceptors DHEA andDHEA-Sarewell-establishedallosteric DHEA actioninneuronal/CNS cells DHEA bindsIGF1Rwasnotexamined. not PKAorCREB DHEA activationofreceptors

h of DHEA treatment, was mediated by DHEA metabolites h ofDHEAtreatment,wasmediatedby DHEA metabolites Published byBioscientifica Ltd. . MutationandalteredactivityofNMDAreceptors . TheNMDAreceptorisaPMcomposed A A Rs)areheteropentamericligand-gatedchloride ), andsigma-1receptors (Traish (Ghasemi . Thesigma-1receptorisa 25 in vitro etal. (Liang etal. and with major depressive and bipolar

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Journal of Molecular Endocrinology primary humanneuralstemcellsderivedfromthefetal primary and sigma-1receptorstostimulatetheproliferationof (Rybczynska in C6 glioma cells, although the apparent have shownthatDHEA-Scompeteswithasigma-1agonist ligation tosimulatestroke 2004) either prenatalexposuretococaine deficitsinducedinmousemodelsby reverse memory Sachidanandan &Bera2015) in transfectedHEK-293cells GABA DHEA-S actedasanallostericantagonistofarecombinant neurons neocortical intracellular calciuminmouseembryonic for rapidNMDAactivationandsubsequentincreasein specificity forDHEA(1 Mellon 1998) neocortical neurons mouse embryonic in rathippocampalslices that DHEA-S (50 function, including ROS generation. Early studies showed mitochondrial membrane junctions and mitochondrial channels toregulatetheirfunctionandisfoundatER– Sigma-1 also interacts with PM-bound receptors and ion 2004, Hashimoto2013,Ruscher&Wieloch 2015) in response to endoplasmic reticulum stress calcium homeostasisandfunctionsasachaperoneprotein binds totheInsP3receptor(IP3R)andmodulatescellular the endoplasmicreticulum,receptorhasdualroles:it neurons, astrocytes,oligodendrocytes,andmicroglia.In nuclear membrane,mitochondrialandPMin M respectively) 1 nM, and NGF =0.01 binding transmembrane tyrosine kinase receptors ( growthfactor(NGF)- and p75NTRareneurotophin nerve respectively 5.6 ±0.5nM, revealed [ of HEK-293cellswithcDNAsencodingTRKAorp75NTR PC12 cells DHEA-S bind to PM receptors TRKA and p75NTR in et al. and increasedNF- activation ofpSRC,MAPK,PICK,PKC,AKT, cAMP, PKA, was describedasaPMreceptorleadingtosequential activated amembraneDHEAbindingsite,which pheochromocytoma oftheratadrenalmedulla.DHEA in PC12 rat sympathoadrenal cells derived from a cortex (ltNSC http://jme.endocrinology-journals.org DOI: 10.1530/JME-16-0013 Review Other potentialDHEAreceptorshavebeenreported DHEA activationofsigma-1receptorwasshownto 2008) or transient bilateral common carotid artery ortransientbilateralcommoncarotidartery A RandwasshowntoblockGABA (Compagnone &Mellon1998) 3 H]DHEA bindingwith (Lazaridis . This group later reported thatDHEAand etal. ctx . Useofpharmacologicalinhibitorsshowed cells) nM–1 2009) κ etal. B andCREB (Suzuki pM), andnotDHEA-S(upto1 µM) activated NMDA receptors . DHEAactivatedbothNMDA (Gravanis 2011) (Yabuki . etal. (Monnet (Svob Strac r

(Lazaridis (Charalampopoulos ds prough etal. etal. (Meunier &Maurice M and 7.4 ±1.7nM of etal. (Compagnone & andothers Printed inGreatBritain 2015) K . Bycontrast, 2012) d A 1995) was >50 et al. etal. Rcurrents (Maurice . Studies . TRKA 2011) 2012, K µM), d and for µM . .

including increasedphospho-ERK1/2andAKT signaling intransfectedHEK-293cellsandPC12cells, DHEA (100 activated adenylylcyclasetoincreasecAMPinHepG2 that itisspecificallyboundtothePMofPC12cells,and group synthesized a photoreactive DHEA analog, showed specific manner Caco2 colorectalcarcinoma cellsinaTRKA-andp75NTR- deprivation-induced apoptosisinDU145prostateand et al. with itseffectorsRhoGDIandRIP2 andtheinteractionofp75NTR TRKA phosphorylation well asinDU145prostatecancercellsandincreased the expressionofTRKAreceptorinPC12cellsas respectively K neurotrophin receptorsexpressedinHEK-293cellswith DHEA bindsLtrk,ApTrk, orAmphiTrk invertebrate et al. and/or physiologicaleffects incardiovascularand contraction andrelatestothetherapeuticaction artery that thisaccountsforDHEA inhibitionofpulmonary cell line cells-somatic mouseneuroblastoma/rat glioblastoma CaV3.1, CaV3.2,orCaV3.3intransfectedNG108-15 (10 in cardiovascular diseaseinhighlycontroversial(reviewed Whether DHEA/DHEA-Sisbeneficialontheoutcome of CaV3.1, CaV3.2,orCaV3.3 DHEA inhibitsvoltage-gatedT-type Ca DHEA actionintheheart interacts withSRC,BRB2,andPKA and aging-relateddeficitsinrats MAP2 is involved in schizophrenia polymerization andstabilizesmicrotubules,lossof brain microtubules, andMAP2ishighlyexpressedinthe (MAPs) promotetubulinpolymerization and stabilize (Laurine interaction withahydrophobicpocket microtubule-associated proteinMAP2C DHEA was reported to bind to the dendritic brain DHEA bindsMAP2C human hepatomacells DHEA activationofreceptors d Published byBioscientifica Ltd. M ad 0.47 ±0.18nM, and 1.14 ±0.11nM, 3.6 ±0.4nM, : µM) inhibitedvoltage-gatedT-type Ca Savineau 2011) 2013) (Sánchez et al. (Chevalier . Morerecentstudieshaveshownthat[ nM for20 . DHEA(100 etal. (Pediaditakis 2003) etal. (Anagnostopoulou 2013,Mannic etal. . The microtubule-associated proteins 2000). min) inducedTRKAandp75NTR (Waschatko Downloaded fromBioscientifica.com at10/03/202112:09:15AM etal. 2012) nM for24 MAP2promotestubulin 2015) . Theauthorsconcluded (Ma (Lim etal. etal. etal. (Shelton etal. . DHEAupregulated h) inhibitedserum 56 2+ (Anagnostopoulou etal. channels: : 2011). 3 2013) 2014) 2015) in vitro 2+ et al. 2013). channels: K . Another (Lazaridis . MAP2C d . DHEA =27µM R149 2015) by 3 H] via freeaccess

Journal of Molecular Endocrinology to cleartheliverofhighlevels ofsterols,includingDHEA. activation leadstotheinduction oftheenzymesneeded sensors ofexcessiveaccumulation ofsterols,andtheir (Webb to thoseinducedbydrugs andchemicaltoxicants in foreigncompoundmetabolismbyDHEAiscommon evidence thatinductionoftheenzymesnormallyinvolved its metabolitesonhepaticmetabolismhaveprovided metabolism andthebiologicalactionofDHEA during adrenarche andparturition.OurstudiesofDHEA is requiredtorapidlyproducethesex-relatedhormones 2008, Rege&Rainey2012) be overlooked DHEA andDHEA-Sassources ofbulkandrogencannot action toberesolved.Thephysiologicalroleofcirculation questions aboutitspossiblemolecularmechanisms of animal, and cell-based studies, there remain many numerous studies of DHEA’s effects in a variety of human, Reviewing theliteraturemakesitclearthatdespite Conclusions mechanism waselucidated. mouse corticalneurons in humanSH-SY5Yneuroblastomacellsandprimary membrane potential, and oxygen consumption rate (OCR) increased ATP synthesis,ROSproduction,mitochondrial (Correa generation, calciumrelease,andpermeabilitytransition mitochondrial membranepotential,andincreasingROS inhibiting NADHoxidation,ATP generation,and complexIinisolatedratkidneymitochondria, respiratory (166 on mitochondrialmembranes reoxygenation, uncoupling,andapoptosis by a directeffect function in response to stresses, including anoxia– DHEA (1 µM) theisolatedratbrainmitochondrial preserved DHEA regulation ofmitochondrial function 2002, 2004) for example,NOSactivationinHUVECs the possiblemechanismsinvolved from cell-basedstudies, epidemiological studies after correctingforusualconfoundingfactorsinmultiple and cardiovascularrisk,morbidity, andmortality, even The authorsreportaninverseassociationwithDHEA-S in cardiovasculartissues(reviewed involving PPAR neuronal diseases.However, DHEAhasadditionalactivities DOI: 10.1530/JME-16-0013 http://jme.endocrinology-journals.org Review µM) was reported to act like rotenone and inhibit µM) wasreportedtoactlikerotenoneandinhibit etal. etal. , 2006) althoughmostarenotdetermined. 2003) (Rainey α , sigma-1R,andunknownmechanisms . The NRs involved appear to serve as . TheNRsinvolvedappear to serve . DHEA(10and100 et al. (Mannic (Grimm , becauseasource ofandrogen 2004, Rainey & Nakamura (Morin etal. r

prough Mannic 2015) et al. 2014) andothers Printed inGreatBritain (Liu &Dillon 2002). nM for24 . Theyreview etal. , but no , butno 2015) DHEA DHEA h) h) . DHEA byDillonandcoworkers andactivatePPARdephosphorylate high concentrations for longer times activate PP2A to and downstreamtoMAPKorotherpathways,whereas activate membranereceptorsleadingtoEGFRactivation time-dependent manner. For example, low DHEA may to low(nM)versussupraphysiological(µM)DHEAina receptors andNRs,thataredifferentiallyresponsive mediated bydifferentreceptors,forexample,PM-bound in theliver, theremaybebiphasicactivitiesofDHEA as thereviewofliteratureherein,wespeculatethat (Traish insomemodelsofobesityandcancer of DHEAobserved (through CARandPXR),leadingtothebeneficialeffects acid metabolism(throughPPARs) anddrugdetoxification resultspossiblyaccountfortheenhancedfatty These activation weregreatlyexpanded.Inaddition,thisand the possiblereceptorfamiliesavailableforDHEA impartiality ofthisreview. There is no conflict of interestthat could be perceived as prejudicing the Declaration ofinterest and itssulfatedforminneurobiologicalfunction. are warranted to fully understand the role of this sterol and time/tissue-dependentdownstreameffectsofDHEA receptors. However, futurestudiesaddressingtheaffinity direct interactionofDHEAwithNRsandPM-associated 2015). Tables 1 and2 and cognitionhavebeenrecentlyreviewed 2015). DHEA concentrationsreportedinthebrain used concentrationsofDHEA(50 et al. neurosteroid anditseffectsincognitivefunction regulation ofhundredsdownstreamgenes. transcriptome, whichwouldthentheoreticallyleadto a cell or tissue) studies are needed to define the miRNA RNA seq(RNAsequencingoftheentiretranscriptome activation ofgeneexpressionbyreceptors.Systemic DHEA actionthatisuniquetoitsroleintranscriptional potently upregulatesmiR-21opensanewmechanismfor thatDHEA heretofore notrealized.Ourrecentobservation sterol in the circulation, may have many functions appreciation thatDHEA,whichisthemostabundant signaling systemshavesincebeendefined,providingan itself maybeasignalingmolecule.Aseriesofdifferent suggestthepossibilitythatDHEA-S other observations DHEA activationofreceptors Published byBioscientifica Ltd. With theidentificationofaG-coupled receptorfor Although thereisgreatinterestinDHEAasa 2015) ThebiologicaleffectsofDHEAinthebrainonmood etal. , somestudiesonthesigma-1receptorhave 2011) . Basedonourrecentstudiesaswell summarizewhatisknownaboutthe Downloaded fromBioscientifica.com at10/03/202112:09:15AM µM) thatarehigherthan (Liu &Dillon2002) α andCAR. 56 : 3 (Pluchino (Hill (Maggio R150 etal. etal. via freeaccess ,

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