ContentslistsavailableatScienceDirect
The
International
Journal
of
Biochemistry
&
Cell
Biology
j ourna l h o m e pa ge :w w w . e l s e v i e r . c o m / l o c a t e / b i o c e l
Redox
signaling
and
oxidative
stress:
Cross
talk
with
TNF-related
apoptosis
inducing
ligand
activity
Rebecca
Voltan
1,
Paola
Secchiero
1,
Fabio
Casciano,
Daniela
Milani,
Giorgio
Zauli,
Veronica
Tisato
∗DepartmentofMorphology,SurgeryandExperimentalMedicineandLTTACentre,UniversityofFerrara,ViaFossatodiMortara70,44121Ferrara,Italy
a
r
t
i
c
l
e
i
n
f
o
Articlehistory: Received29June2016 Receivedinrevisedform 21September2016 Accepted24September2016 Availableonline26September2016 Keywords: TRAILpathway Redoxpathway Inflammation Endothelialdysfunction Cancer
a
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c
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Redoxregulationplaysakeyroleinseveralphysiopathologicalcontextsandfreeradicals,fromnitric oxideandsuperoxideanionuptootherformsofreactiveoxygenspecies(ROS),havebeendemonstrated tobeinvolvedindifferentbiologicalandregulatoryprocesses.Thedatareportedinthecurrentliterature describealinkbetweenROS,inflammationandprogrammedcelldeaththatisattractinginterestas newpathwaystobeexploredandtargetedfortherapeuticpurposes.Inthislight,thereisalsogrowing attentiontotheinvolvementofthislinkintheactivityoftheTNF-relatedapoptosisinducingligand (TRAIL).TRAILisamemberoftheTNFligandssuperfamilyabletomediatemultipleintracellularsignals, withthepotentialtoleadtoarangeofbiologicaleffectsindifferentcelltypes.Inparticular,thehallmark ofTRAIListheabilitytoinduceselectiveapoptosisintransformedcellsleavingnormalcellsalmost unaffectedandthisfeaturehasalreadyopenedthedoortoseveralclinicalstudiesforcancertreatment. Moreover,TRAILplaysaroleinseveralphysiologicalandpathologicalprocessesofbothinnateand adaptiveimmunesystemsandofthecardiovascularcontext,withastrongclinicalpotential.Nonetheless, severalissuesstillneedtobeclarifiedaboutthesignalingmediatedbyTRAILtogaindeeperinsightintoits therapeuticpotential.Inthislight,theaimofthisreviewistosummarizethemainpreclinicalevidences abouttheinterplaybetweenTRAILandredoxsignaling,withparticularemphasistotheimplicationsin vascularphysiopathologyandcancer.
©2016TheAuthors.PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction
The “redox signaling” is a complex regulatory process in
whichthesignalis deliveredthroughredox chemistryin order
togenerate protective responsesagainst oxidative damage and
restorethecorrectredox-balancebetweenreactiveoxygenspecies
(ROS)productionandtheirclearancebyanti-oxidative/scavenging
mechanisms(Droge, 2002).In this light, theoriginal definition
of oxidative stressrefers to an unbalanced condition,resulting
fromexcessiveproductionofROS andreactivenitrogenspecies
(RNS)thatantioxidantdefensesystemsarenotableto
counter-act,leadingtoaccumulationofreactivespeciesthatplay a role
inseveralpathologicalcontextsincludinginflammation,
cardio-vascular pathologies, atherosclerosis, metabolic alterations and
cancer(MontezanoandTouyz,2012a;PanieriandSantoro,2016).
Nonetheless,theconceptofoxidativestressisfarmorecomplex
∗ Correspondingauthor.
E-mailaddress:[email protected](V.Tisato).
1 Equallycontributed.
anditsdelineationhasimprovedintherecenttimeswiththeaimof
includingtheroleofredoxsignalingandreactivespecies/molecular
redox mediators, defining a research field connecting multiple
disciplinesincludingchemistry,cellbiologyandphysiopathology
(Sies,2015).Thisnewdeclinationoftheconceptofoxidativestress
accountsfortheincreasingevidencesoftheinvolvementof
reac-tivespeciesinkeyregulatorynetworksofphysiologicalfunctions
suchasregulationof vasculartone,insulinsynthesis,activation
ofhypoxia-induciblefactor,cellproliferation,differentiationand
migration (Weidingerand Kozlov, 2015), suggestingthat redox
biologymightunderlieandincludebothphysiologicaland
patho-logicalcontexts(SchieberandChandel,2014).Intheabsenceof
awidelyacceptedsystemforclassificationofoxidativestress,a
“intensity-based”classificationhasbeenproposed,highlightingthe
roleofthedose/concentrationofthe“stress-inducer”inrelation
tomolecular/biologicalendpointparametersevaluatedthatreflect
themodificationsinducedbyROS(Sies,2015;Lushchak,2014).
Inthiscontext,theendotheliumrepresentsabiologicalmilieu
that in normal conditions maintains its integrity and
function-ality through a tight balance between opposite signals and
http://dx.doi.org/10.1016/j.biocel.2016.09.019
1357-2725/©2016TheAuthors.PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4. 0/).
pathways including anti/pro-oxidative, anti/pro-vasodilators,
anti/pro-inflammatory, anti/pro-thrombotic,
anti/pro-proliferative signaling (Vanhoutte et al., 2009). In the recent
years, several in vitro and in vivo reports have demonstrated
that the tumor necrosis factor-related apoptosis inducing
lig-and (TRAIL) plays an important role in vascular physiology by
triggering different pathways, with a protective effect on the
vascularwallsandonendothelialbarrierfunction.However,
con-flictingresultsemergesinceTRAILisamoleculeabletoactivate
pro-apoptotic/pro-inflammatorypathwaysbut also pro-survival
andanti-inflammatorycellsignals. Thisduality isa hallmarkof
theTRAILactivityandthedatareportedabouttheroleofTRAIL
on atherogenesis represent a paradigm of this feature (Cheng
etal., 2014).In fact,while a possibleprotectiveeffect ofTRAIL
has emerged from preclinical and clinical studies (Di Bartolo
etal.,2011;SecchieroandZauli,2012),highTRAILlevelsmight
result in a detrimental effect on vascular integrity leading to
a pro-atherogenic condition, perhaps by enhancing leukocytes
adhesionandlocalinflammatoryprocessesinapathogenicloop
supporting plaques formation (Michowitz et al., 2005), leaving
still partially unclearthe mechanisms underlyingthese effects.
On thecontrary, in thecontext of cancer, recombinant soluble
TRAILalreadyrepresentsanappealingtherapeuticoptionthatis
underevaluationattheclinicallevelforthetreatmentofdifferent
typesoftumor(StuckeyandShah,2013;Gasparinietal.,2013;
Lemkeetal.,2014).However,eventhoughencouragingresultsare
comingfromtheassessmentofitstherapeuticpotential,several
issues still need to be addressed suchas the needto enhance
TRAILantitumoractivityinordertoovercometheheterogeneous
sensitivityoftumorsandtorestorethecellsensitivitytoTRAILin
thepresenceofTRAIL-resistancemechanisms.
Intracellularreactivespeciesandcomponentsoftheredox
sig-naling couldbe critical in regulating the response to TRAIL in
differentphysiopathologicalcontexts.Inthislight,itisofinterest
thatROScaninfluenceinductionofapoptosismediatedbyCD95
andTRAILbyaffectingexpressionanddistributionofcell
recep-tors,makingtheconnectionbetweenredoxsignalingand death
receptorsanimportantmechanismofcellregulationwith
signif-icantimplications.In thiscontext,inorder toshedlight onthe
interplaybetweenTRAILandoxidativepathway,wesetoutthis
reviewtosummarizethemainpreclinicalevidencesofthis
inter-actionfocusingontwoofthemainphysiopathologicalcontextsof
theTRAILactivity:thevascular/endothelialcompartmentandthe
tumorsetting.Moreover,wewillreviewanddiscussthekey
sug-gestionscomingfromtheassessment ofthecrosstalkbetween
TRAILandredoxsignalinginordertounderstandthe“TRAIL
biol-ogy”intermsofmolecularmechanismsofactionandstrategiesto
exploitthepotentialofTRAILastherapeuticmolecule.
2. OverviewonTRAILsignalingandbiology
TRAILis a member of theTNF ligandsuper family that can
bedescribed asapleiotropicmoleculeabletomediatemultiple
intracellularsignalswiththepotentialtoleadtodifferent(quite
oftencontradictory)biologicaleffects.ThisfeatureofTRAILclearly
emergesfrombothpreclinicalresultsandclinicalstudies
highlight-ingthe“dual-role”ofthisproteininseveralpathologicalconditions,
spanningfromimmunological/cardiovasculardisorderstocancer.
Discoveredindependentlybytwogroupsmorethan20yearsago
(Wileyetal.,1995;Pittietal.,1996),severalsubsequentinvitro
andinvivofunctionalstudiesshowedthatTRAIL(alsoreferredas
Apo2,CD253andTNFSF10)wasabletotriggercellapoptosisin
tumorcells orinfected/transformedcellswhileleaving
substan-tiallyunaffectednormalcells(Ashkenazietal.,1999;Walczaketal.,
1999).Althoughthis concept ofselective pro-apoptoticactivity
hasbeenrevised duringtime asit hasbeen reportedthat also
somenormalcellscanbeaffectedbyTRAIL(Vanhoutteetal.,2009;
Ursini-Siegeletal.,2002;Nesterovetal.,2002;Hayakawaetal., 2004;Janssenetal.,2005;Zaulietal.,2009).TRAILisexpressedin
awiderangeoftissuesinbothhealthyanddiseaseconditionsand,
incommonwithothermembersoftheTNFfamily,canbedetected
astrans-membranetypeproteinandassolubleprotein(Liabakk
etal.,2002).Onceexpressed,theproteincanbecleavedandact
assolublemoleculethroughthegenerationofcirculatingtrimers
thatrepresentthebiologicallyactiveformofTRAILviainteraction
withasystemoffivereceptorswhichcanbeboundwithdifferent
affinities(OrlinickandChao,1998;Yerbesetal.,2011).In
partic-ular,theTRAIL-receptorsystemcomprises:twotransmembrane
pro-apoptoticdeathreceptors(DRs)named TRAIL-R1(DR4)and
TRAIL-R2(DR5)displayingfull-lengthintracellulardeathdomain,
twotransmembranedecoyreceptorsnamedTRAIL-R3(DcR1)and
TRAIL-R4(DcR2)lackinganintactdeathdomainandthesoluble
decoy receptor osteoprotegerin (OPG) lacking both
transmem-braneandcytoplasmicdomains(OrlinickandChao,1998;Yerbes
etal.,2011;Falschlehneretal.,2009).ItisofinterestthatmRNA
of alltransmembranereceptors canbe detectedin virtually all
tissues,whilecellsurfaceTRAILproteinexpressionismore
cell-dependent. Asmentioned before, themostintriguingfeatureof
TRAILis itsability toinduceapoptosismainlyin cancerand in
transformed/infectedcellsbyinteractingwithDR4andDR5.The
TRAIL-mediatedapoptosispathwayshavebeenalreadyreviewed
indetails(Falschlehneretal.,2007),brieflyafterbindingtoDRs,
inductionofapoptosisrequirestheassemblyofadeath-inducing
signalingcomplex(DISC)atmembranelevelcharacterizedbythe
clusteringandoligomerizationofintracellulardeathdomainswith
therecruitmentoftheFas-AssociatedDeathDomain(FADD)and
caspases-8and-10thatarerecruitedandundergoautocatalytic
processingfollowedbycaspasescascadeactivation(Sessleretal.,
2013)(Fig.1A).Inadditiontocaspases-mediatedextrinsic
apop-toticprocess,thereisalsoanintrinsicapoptoticsignalingtriggered
bythecleavageoftheBH3-only proteintotruncatedBid(tBid)
thatmediatestheactivationofBaxandBakatthemitochondrial
level with release of Cytochrome-C and pro-apoptotic proteins
(Falschlehneretal.,2007;Sessleretal.,2013)(Fig.1A).
Activation of TRAIL death receptors may also trigger
non-apoptotic and pro-survival/proliferation signals such as those
mediated by the mitogen-activated protein kinases (MAPKs),
PI3K/AktandERKpathwaysandbythetranscriptionfactornuclear
factor-B(NF-B),allinvolvedintheregulationof
developmen-talandinflammatoryprocesses(DiPietroandZauli,2004;Zauli
etal.,2005)(Fig.1A).Finally,aswellasotherpro-apoptoticsignals,
TRAILcanalsoleadtonecroptosis,aregulatedandprogrammed
formofnecrosisputinplaceasresponsetoseverestressandinthe
presenceofblockednormalapoptosis(Jouan-Lanhouetetal.,2012;
Chenetal.,2016).Acomparisonbetweenapoptoticandnecroptotic
processeshasbeenrecentlyaddressedandreviewed,highlighting
theroleofthedifferentnecroptoticregulatorsandpathways(Chen
etal.,2016;FuchsandSteller,2015).Inparticular,theformation
ofthenecroptotic-complexfollowingstimulationismediatedby
specifickinases(RIPK1andRIPK3),thatareinturninvolvedinthe
phosphorylationofthemixedlineagekinasedomainlikeprotein
(MLKL),triggeringtheinductionof downstreamprocesses
lead-ingtocelldeathsuchasalterationofosmoticpressureandplasma
membranerupture(Fig.1A).Ithasbeensuggestedthat
Caspase-8mightbeoneofthekeyfactorsinmediatingtheexecutionof
eitherapoptosisornecrosis.Caspase-8isabletoblock
necropto-sisbycleavingRIPK1andRIPK3infavoroftheapoptoticprocess
whileinthepresenceofCaspase-8inhibitorsand/orcompromised
Caspase-8activitythereisaninhibitionofapoptosisinfavorofthe
necroptoticsignaling.Althoughthemechanismsdown-streaming
Fig.1.SchematicrepresentationofTRAIL-mediatedapoptotic,pro-survivalandnecroptoticsignaling.Afterbindingtoitsreceptors,TRAILcaninitiatecellapoptosis, necrop-tosisorleadtocellsurvival.InA,themainmolecularmediatorsinvolvedinTRAIL-mediatedpathwaysleadingtocellsurvival(viaNF-Bandkinasesactivation),apoptosis (viacaspasesactivation)andnecroptosis(viaRIPK1-3andMLKL)areshown.InB,amodelofaggregationofTRAILreceptorsinlipidraftsleadingtoenhancedTRAIL-induced apoptosisthroughthemediationofROSandASMproductionisshown.ROSarereactiveoxygenspecies;ASMisacidsphingomyelinase;DRaredeathreceptors.
clearthatthepossibilityofpromotingnecroptosisincancercells
representsanattractivetherapeuticstrategywithastrongclinical
potentialthatdeservemoreinvestigations,inparticularinlightof
theevidencethatresistancetoapoptosisisoneofmostchallenging
hallmarksofcancer.
TRAILplaysacriticalroleinmodulatingtheimmunesystemand
thisfeaturehasbeenextensivelyexploredinthecontextofdiabetes
mellitus(DM)(Bossietal.,2015).Inparticular,bothpreclinicaland
clinicalreportsonType-1DMsuggestaprotectiveeffectofTRAIL,
probablythroughtheregulationofcentralandperipheral
toler-ancecarriedoutthroughamodulationofT-cellsactivityachieved
inducingTcellapoptosisandexpansionofregulatoryTcells(Zauli
etal.,2010;Bernardietal.,2012a;Torneseetal.,2014,2015).Inthe
samefashion,TRAILcancontrolType-2DMbycontrastingfatmass
increaseandinducinganti-inflammatoryeffects(Bernardietal.,
2012b;Bisginetal.,2012;Xiangetal.,2014).Theevidencethat
patientsaffectedbyseveraldiseasesshowalteredcirculatingTRAIL
levelshighlightstheinvolvementofTRAILintheonset/progression
ofthediseasessuggestingaclinicalpotentialofthismoleculeasa
diseasebiomarkerorastherapeuticoption.Ourgrouphas
signifi-cantlycontributedtothedemonstrationofaninversecorrelation
betweencirculatingTRAILlevelsandpathologicalconditions
char-acterizedbychronicinflammation.LowTRAILlevelsareassociated
withtotal andcardiovascularmortalityin olderadults (Volpato
etal.,2011),andwithpooroutcomeinpatientsaffectedbyother
pathological conditions suchas myocardialinfarction, coronary
syndrome,heartfailureandchronicdiseases(Secchieroetal.,2009,
2010a;Niessneretal.,2009;Liabeufetal.,2010;Osmanciketal., 2013;Bromboetal.,2013).Overall,thesestudieshavesuggested
thatTRAILmighthavea roleinvascular protectionandcontrol
ofinflammation(Secchieroetal.,2013).Asregardtothe
regula-torymechanismsofTRAILexpression,arolehasbeenidentified
for17-estradiolthatcouldbeinvolveddownregulatingthe
cir-culatinglevelsofTRAIL(Zaulietal.,2014).Otherhypothesesfor
thelowTRAILlevelsdetectedinseveralpathologicalsettings,in
particularinthecontextofcardiovasculardiseases,mightbedue
tothesimultaneousincreaseofcirculatingOPGand/orto
alter-ationsofotherbiologicalparameterssuchasthebalancebetween
metalloproteinase-2andtissueinhibitorofmetalloprotease-2that
hasbeenproposedtobeinvolvedintheclearanceofcirculating
TRAIL(Secchieroetal.,2010b).Nevertheless,aspreviously
men-tionedforatherosclerosis,conflictingresultshavebeenreported
onthe role of TRAILalso for rheumatoid arthritis (Audo et al.,
2013),allergicasthma(Tisatoetal.,2014;Collisonetal.,2014)and
inflammatorydisorders oftheCNSlikelyastheresultof
differ-entinvolvement/effectsofTRAILpathwaysinlocalandperipheral
inflammatoryprocesses(Tisatoetal.,2016).Overall,theemerging
picturedescribesTRAILasamoleculeabletotriggeramultifaceted
systemofbiologicaleffectsandfunctions,asresultofacomplex
ligandreceptors’systemandofmultiplelevelsofsignal
modula-tion/controlthatareputinplaceaccordingtothespecificcelltype
andtothespecificbiological/pathologicalcontexts.Inthisline,
cur-rentdatasuggestthatDRsaredefinitelymorethansimplyreceptors
involvedintriggeringanapoptoticsignal,sincetheiractivationcan
leadtoawidepanelofcellularresponses.TheabilityofDRsto
mediateconflictingcellsignalsmightbealsotheresultofthe
redis-tributionofDRsthemselvesatthecellmembranesurfaceoftarget
cells,withimportantbiologicalandtherapeuticimplications.The
distributionofthedifferentreceptorscouldaccountforthe
selec-tiveactivityofTRAIL,whichmightbecontrolledbythetemporal
andlocalredistributionofitsreceptors.Infact,thefunctionality
ofligandreceptors,suchasthoseforTRAIL,involvestheir
phys-icalassociationatthemembranelevelthroughthegenerationof
membranedomainsdefined“rafts”.Thesemembranedomainsplay
akeyroleinthetransductionoftheextracellularsignalsinsidethe
targetcellandhaveastrongpotentialasatargetfornewstrategies
tocontrolcelldeathandovercomeTRAIL-resistance(Delmasetal.,
2004).
2.1. TRAILandredoxpathwaysinterplay:roleinvascularcells
biology
2.1.1. TRAIL/TRAIL-receptorsandendothelium
TheselectivemechanismsmediatedbyTRAILleadingto
apo-ptosis almost exclusively of cancer cells and to activation of
non-apoptoticpathwaysarestillunclear(BakerandReddy,1996;
Zhang etal., 2000;Pritzker et al.,2004; Ashkenaziand Herbst,
2008).Inthisline,theongoingliteratureclearlydocumentsthat
alsointhecontextofvascularphysiopathologytheroleofTRAIL
remainscontroversial,withanoverallmessagecoherentwiththe
“dual-face”nature ofthis protein. TRAILis expressedin
vascu-larsmoothmusclecells(Gochuicoetal.,2000),andalthoughthe
expressionofTRAILproteinattheendotheliallevelisstilla
presenceofallTRAILreceptorsinthesecellsis abletomediate
a broad range of reactionsupon stimulation by TRAIL,
includ-inginflammation,apoptosis,cellproliferationanddifferentiation
(ZauliandSecchiero,2006;Cantarellaetal.,2014).Ontheother
hand,theclinicalevidencethatcirculatingTRAILlevelscorrelate
withseveralpathologicalconditionswitha vascularcomponent
supportstheinvolvementofTRAILintheonset/progressionofthese
diseases,withdifferentvisionsaboutitsrole(Tisatoetal.,2013;
Harperetal.,2016;Fordeetal.,2016).Inthiscontext,ourgroup
hascontributedtothedemonstrationthatTRAILisabletopromote
survivalandproliferationofprimaryhumanendothelialcells(Zauli
etal.,2009;Secchieroetal.,2003).Inparticular,thepro-survival
signalsaremediatedbyphosphorylationoftheserine/threonine
kinaseAktviaPI3KactivationandbythestimulationofERK1/2
pathway(Secchieroetal.,2003).Infact,indifferentinvitro
stud-ies,theinhibitionofphosphatidylinositol3-kinase(PI3K)wasable
toreduceP-Akt, witha concomitant reduction ofBcl-2 leading
tothesensitizationof theendotheliumtoTRAIL-mediated
apo-ptosisviaextrinsicandintrinsicpathways(Secchieroetal.,2003;
Alladinaetal.,2005).Moreover,wehavealsodemonstratedthat
TRAILdownmodulatestheinteraction/adhesionbetween
leuko-cytesandendothelialcells,counteractingthepro-adhesiveactivity
ofbothTNF-␣andIL-1byselectivelydown-regulatingCCL8and
CXCL10chemokines,withbothTRAIL-R1andTRAIL-R2playinga
roleintheTRAIL-mediatedeffects(Secchieroetal.,2005).
2.1.2. TRAILandROSinendothelium
Impaired/inefficient activity of antioxidant systems such as
endothelial-derivedvasodilatorsmayleadstoROSaccumulation,
celldamageandtoavarietyofpathologicallesions(Sies,1997;Cai
andHarrison,2000).Inthisrespect,thereisawidelyacceptedlink
betweenoxidativestressandinflammationatthevascularlevel,
leadingtoendothelialcelldysfunctions(e.g.compromisedability
toregulatethevasculartoneandalteredpro-coagulantand
anti-inflammatorycapacities),whicharefeaturesofatherosclerosisand
vasculardiseases(Ross,1999;Higashietal.,2014;Sitietal.,2015).
MajorsourcesofcellularROSincludethemitochondrialrespiratory
chainandenzymaticreactionsmediatedbyenzymesystemssuch
asxanthineoxidoreductase,nitricoxide(NO)synthase(NOS)and
nicotinamideadeninedinucleotidephosphate(NADPH)oxidases.
Thephysiologicalandpathologicalrelevanceofthesesourcesis
dif-ferentdependingonthespecificdiseaseandtissue/organ.Within
the enzymesresponsible for ROS production, NADPHoxidases,
xanthineoxidasesand(uncoupled)NOSareofparticularly
impor-tanceintheendothelial/vascularcompartment.Atvascularlevel,
primaryROSproducts,mainlysuperoxide(O2−)andhydrogen
per-oxide(H2O2), are indeed involved in a broad range of cellular
functionsrelated toendothelialfunctions/dysfunctionsand
vas-cular functional integrity including cytoskeletalregulation, cell
proliferation, differentiation,migration and apoptosis (Lassegue
andGriendling,2010;MontezanoandTouyz,2012b;Raazetal.,
2014).A keyrole in endothelialcellbiologyand cardiovascular
homeostasisisplayedbyNO,aRNSsynthetizedfromL-Arginine
andinvolvedintheregulationofthevasculartone,andanomaliesin
theproduction/bioavailabilityofNOarefeaturesofendothelial
dys-functionsassociatedtocardiovasculardiseases(Zhaoetal.,2015).
At endotheliallevel NO modulates severalprocesses, including
plateletaggregation,leukocyteadhesion,vascularsmoothmuscle
cellproliferationandangiogenesis(Moncadaetal.,1991;Dimmeler
andZeiher,1999;Dimmeleretal.,1999;Fisslthaleretal.,2000; Vasaetal.,2000;Weilandetal.,2000).Inthisrespect,ourgroup
hasdemonstratedthatTRAILisabletoinducetheproductionof
NOupregulatingendothelialNOS(eNOS,themostimportant
enzy-maticsourceofNOinvascularendothelialcells),byactivatingofthe
Akt/eNOSpathwayandincreasingtheproductionofprostanoids
viacyclooxygenase-1,conferringtothecellsaproangiogenicand
anti-inflammatoryphenotype(Zaulietal.,2003).However,atthe
sametime,ininvitroendothelialcellsystemsothergroupsshowed
that TRAIL was alsoable to triggerFADD-caspase-8-dependent
apoptosistogetherwiththeinductionofinflammatorypathways
includingNF-BactivationandE-selectin,ICAM-1,andIL-8
expres-sion(Lietal.,2003).Inthesamefashion,intheirworkPritzkerand
colleaguesdemonstratedthatTRAILwasabletoinduceapoptosis
inhumanmicrovascularendothelialcellswhileitsdecoyreceptor
OPGactedassurvivalfactor(Pritzkeretal.,2004).Morerecentlyin
thepathologicalcontextofAlzheimer’sdisease,thepro-apoptotic
deathreceptorsDR4andDR5wereshowntomediatetheinduction
ofextrinsicapoptoticpathwaywithactivationofbothcaspase-8
andcaspase-9inhumanmicrovascularcerebralendothelialcells
(Fossatietal.,2012).Takentogetherthesedataoverallsuggestthat,
attheendotheliallevel,TRAILmighthavetheabilitytopromote
opposite signalingpathways actingeither as pro-apoptotic
sig-naloraspro-survival/anti-apoptotic/anti-inflammatorystimulus,
encouragingtheongoingdiscussion.
2.1.3. TRAIL-receptorsandROSinendothelium
ThereportedcontrastingeffectsmediatedbyTRAIL,inboth
nor-malandpathologicalconditions,havebeenalsoassociatedtothe
conceptofthesocalled“lipid rafts”,morerecentlydesignedas
“membraneraft”(MR).MRaredynamiccellmembranedomains
based on cholesterol, proteins and
sphingolipids/sphingolipids-metabolitesthatareabletomediateseveralcellfunctions(Zhang
etal.,2009).TheMRconstitutionisstrictlyrelatedtothe
genera-tionofceramideviahydrolysisofmembranesphingomyelinbyacid
sphingomyelinase(ASM),akeyeventthatsignificantlymodifyboth
cell membrane constitutionand propertiesthrough themutual
interactionbetweensphingolipidsandbetweensphingolipidsand
cholesterolresultingintheformationofdistinctmembrane-area.
Thefusionofdifferentsmallceramide-richmembraneareasleads
tothegenerationofmorelargeceramide-enrichedmembrane
plat-formsthatorganizethelocalandtemporaldistribution/clustering
ofcellreceptorsandsignalingmoleculesdrivinginthiswaythe
transmissionofspecificcellsignalsandthemodulationofthe
asso-ciated cell-pathways amplifying receptor- and stress-mediated
signalingevents(Zhang etal., 2009).It is ofinterest thatthere
is a specific link between ceramide-mediated MR constitution
and redox signalingat thevascular level witha crucial role of
ceramideinamplifyingredoxsignalinginendothelialcellsleading
toendothelialdysfunction(Lietal.,2010;Jinetal.,2011).Inthis
respect,ithasbeenshownthatceramide-reachplatformshavean
impactinROSproductionsincetheyareabletorecruitand
acti-vatekeymoleculesinvolvedinROSproductionsuchastheNADPH
oxidasefamily,gp91phox,p47phox,RacGTPase(Zhangetal.,2006,
2007;Jinetal.,2008).Moreover,theformationofMR-redox
signal-ingplatformsinendothelialcellsisassociatedwithaproductionof
ceramide,mediatedbylysosomalASMthattranslocateatthecell
membranelevelafterlysosomaltraffickinginresponseto
death-receptorsactivation(Baoetal.,2010a,b).
In thecontextof TRAIL,thegenerationofspecificlipid rafts
seemstobeoneofthepossiblemechanismsofactionbywhich
this ligandisabletotriggerdifferentcellularpathwayswithso
different cellulareffects. TRAIL hasbeen demonstrated to
acti-vateASMviaaredoxmechanismresultinginreleaseofceramide
and formation of ceramide-enriched membrane platforms that
are involved in the clustering of DR5, that amplify TRAIL-DR5
signaling(Dumitruand Gulbins,2006)(Fig.1B).In fact,intheir
studyDumitruandcolleaguesshowedthatantioxidantswereable
topreventASMstimulationand thereleaseofceramide
follow-ingTRAILtreatment,leadingtoabrogationofceramide-enriched
membrane platforms formation and inhibiting TRAIL-induced
apoptosis(DumitruandGulbins,2006).Morerecently,Liand
membranere-organizationprocessesinthecontextofendothelial
cells(Lietal.,2013).Inamodelofmurinecoronaryarterial
endothe-lialcells(CAECs),theauthorsshowedthatTRAILwasabletoinduce
theformation ofredox-MRplatformswithactivationofNADPH
oxidaseandproductionofO2−,leadingtoendothelialdysfunction
andvasodilatation(Lietal.,2013).Theproposedmodelhighlights
DR4astheTRAILreceptorinvolvedandresponsible,upon
activa-tion,ofanearly-stageandacuteeffectthroughtheinductionof
theassemblyandactivationofNADPHoxidaseinMRclusters.In
particular,theauthorsshowedthatTRAILwasabletotriggerthe
fusionoflysosomeswiththecellmembranewiththeformationof
MRredoxplatformsrichinceramideleadingtoimpaired
endothe-lialfunctions.Ofinterest,theresultsobtainedinthesamemodel
butinacontextofASM-deficiencyconfirmedthekeyroleofASMin
mediatingtheTRAIL/DR4-inducedformationoftheredox-MR
plat-formsandthesubsequentendothelialdysfunction.Thereported
cellalterationswereassociatedtoincreasedO2−levels,leadingto
areducedavailabilityofNOwithdeficiencyonvasodilatation(Li
etal.,2013).
IncontrasttothecytotoxiceffectofTRAILassociatedwithROS
production,ithasbeennonethelessreportedthatROSmightbe
involvedinTRAIL-inducedprotectiveandanti-apoptoticeffect.Di
Bartoloandcolleagueshaverecentlyreportedtheresultsofastudy
aimingatunderstandthemechanismsofTRAILininducing
angio-genesisandneovascularization(DiBartoloetal.,2015)showing
thatNADPHenzymes,thekeyfactorsforROSproductionin
vas-cularcells, might triggerotherbiological effects. In a model of
angiogenesisfollowinghindlimbischemia,theauthorsreported
aproangiogeniceffectofTRAILasdownstreamregulatorof
FGF-2,and highlighted thelink betweenthe NADPHoxidase-4 and
NOsignaling.Inparticular,endothelialcellproliferation,migration
andtubuleformationuponTRAILstimulationweredependenton
H2O2andeNOS-derivedNOsignals(DiBartoloetal.,2015).Asthe
authorssuggestinthediscussion,thedifferentresultsobtainedin
theirmodelcomparedtothefindingsreportedbyLiandothers,
mightbeduetotheactivationofspecificNADPHoxidaseisoforms.
Inthislight,inanon-endothelialmodelithasbeendemonstrated
thatbothDR4andDR5canactivateNADPHoxidase-1andtrigger
anapoptoticpathwayviariboflavinkinaserecruitment,following
analternativemechanismofsignaltransductionfromthe
conven-tionalDISC-mediatedapoptosis(Parketal.,2012).
SeveralreportshaveindeedhighlightedthatNADPHoxidases
activationbyhighglucoseleadstoincreasedROSproductionwith
endothelialdamage/dysfunction, and alteration of theintegrity
of theendothelium byreducing NO bioavailability (
Bonnefont-Rousselot,2002;Nakagamietal.,2005;Yuand Lyons,2005).In
thiscontext,Liuandco-workershaverecentlydemonstratedthat
recombinantTRAILsignificantlyattenuatedendothelialcell
apo-ptosisandoxidativestressinducedbyhighglucoseinbothininvitro
andinvivoexperimentalmodels(Liuetal.,2014).Inparticular,
TRAILwasabletosuppresssuperoxideproductioninaninvivo
modelofhigh-glucosestressbyinducingasignificantincreaseof
superoxidedismutase(SOD)activity.Moreover,theinvitrodata
showedthatTRAILreducedhigh-glucosemediatedROS
produc-tionbysuppressingNADPHoxidaseactivityandbyincreasingthe
expressionofprotectivefactorsincludingSOD2andGPx-1.
Sig-nalpathwaysstudiesfinallysuggestedthatTRAILtreatmentcould
attenuatethedamageinducedbydiabetesattheendotheliallevel
throughtheinvolvementandactivationofthePI3K-Akt-eNOS
sig-nalingpathways(Liuetal.,2014).
Overall,thelinkbetweenTRAILandNOthroughthe
PI3K-Akt-eNOSsignalingpathwaysappearsoneofthemolecularnetworks
involvedin theprotectiverole ofTRAIL assupportedby
differ-entgroupsofinvestigators.Nonetheless,theinteractionbetween
TRAILandceramideemergesaswellasacriticalsignaling
path-way in regulating thebiological effects at endothelial level. In
particular,deeperinsightintothecrosstalkbetweenTRAILand
redoxsignals,inMR platformformationandinTRAIL-receptors
clusteringprocessesareneededtogetherwithabetter
understand-ingofthemechanismsofactionofTRAILinrelationtothedifferent
NADPHisoformsandROSgenerationpathways.
2.2. TRAILandredoxpathwaysinterplay:roleintumorbiology
2.2.1. TRAIL/TRAIL-receptorsandtumors
In thefield of cancer therapy, TRAILhas obtainedin recent
years tremendous interest due toits ability toinduce
apopto-sisinmalignanttumorcellswithoutaffectingnormalcells.This
feature,observed in severalinvitro andin vivomodel systems
of both solid and hematopoieticcancers, indicates TRAIL is an
idealanti-cancerdrug(Walczaketal.,1999;HolochandGriffith,
2009;deMigueletal.,2016).Onthesebases,severalresearchers
developedpharmacologicstrategies,usingrecombinantTRAILor
TRAIL-receptoragonists(TRAs),toexploitthepotentialofTRAILin
clinicalanticancerapplications(Lemkeetal.,2014).Whilethese
therapeuticapproachesareunderevaluationinphaseI/IIclinical
studies(Table1),twomajorissuesstilllimittheclinicaltranslation
ofTRAIL:theevidencethatsometumorsareTRAIL-resistantand
thatcancerscandevelopacquiredresistancetoTRAIL.The
mech-anismsbywhichcancercellsescapeTRAIL-inducedapoptosisare
several(Bunekeretal.,2009;TrivediandMishra,2015)and
innova-tiveapproachestoovercomeTRAILresistancearecurrentlydeeply
investigated.Ofinterest,agrowingnumberofstudiesindicatesthat
TRAILresistantcancercellscanbere-sensitizedbyusingseveral
agents(naturaland syntheticcompounds,FDA-approveddrugs)
targetingspecificintracellularpathways(TrivediandMishra,2015;
Farooqi et al., 2015).Following this recent therapeutic view, a
therapeuticapproachbasedonthecombination ofTRAILplusa
re-sensitizingagentisatpresentthebestopportunitytoimprove
theTRAILanti-tumoractivity.
2.2.2. Deathreceptorsandinflammationincancer
FollowingtheconceptthatTRAILexertsitsactivitynotonlyby
inducingcellapoptosisbutalsobymodulatingotherkeycellular
pathwayssuchasthoseinvolvedpromotinginflammation,
alter-nativecellsignalinghavebeenconsideredandinvestigatedalsoin
thecontextofcancer(TrivediandMishra,2015;CullenandMartin,
2015).TheengagementofTRAILreceptors(andFas)candrivethe
productionofpro-inflammatorycytokinesandchemokinesafter
NF-Bactivation(Zaulietal.,2005;Trauzoldetal.,2001;Siegmund
et al.,2005; Berget al., 2009), with importantimplications for
severaldiseaselinkedtochronicandacuteinflammationandfor
cancerbiology(TrivediandMishra,2015;Chenetal.,2010).
Con-sideringthatNF-Bactivationandproteintranslationareinhibited
duringtheapoptoticprocess,thenon-apoptoticeffectsofTRAIL
are more evident in apoptosis-resistant cells that can acquire
metastatic/invasivepotential,asshowninseveraltumortypessuch
as in pancreaticductaladenocarcinoma (Trauzold et al., 2006),
cholangiocarcinoma(Ishimuraetal.,2006),melanoma(Takahashi
et al., 2013) and breast cancer (Wang et al.,2014).Besides, in
additiontoitsanticancerrole,TRAILmightalsopromotethe
inflam-matorytumormicroenvironment.Inthislight,arelevantpaperof
BergandcolleaguesshowsthatTRAILactivatespro-inflammatory
pathwaysin50%ofprimarymyelomasamples,emphasizingthe
evidence that TRAIL shouldbe used in combination with
anti-inflammatorydrugstoreducethepro-inflammatoryeffectsofthe
molecule(Berget al.,2009).Coherently withthis suggestion, it
hasbeen demonstrated that NF-B activation canpromote the
expressionofinterleukins(suchasIL-1,IL-8andIL-6)thatexert
a growthpromotingeffect onthetumor,even though therole
ofNF-Bis stillcontroversialin sometumortypes(Ben-Neriah
Table1
ClinicaltrialswithagonisticantibodiesorsolubleTRAILreportedonwww.clinicaltrials.gov.
Cancer n Combination Phase Status Identifiern◦
Conatumumab(AMG655)
Colon 202 ModifiedFOLFOX6,Bevacizumab,Placebo I/II C NCT00625651
Colon 53 Panitumumab I/II C NCT00630786
Colon 155 AMG479,FOLFIRI,Placebo II C NCT00813605
Colon 12 AMG479,Ganitumab,Bevacizumab II A(nr) NCT01327612
Colon,Lung,Ovarian,Pancreatic,Sarcoma 89 AMG479 I/II T NCT00819169
Hodgkin’slymphoma,NHL 33 Vorinostat,Bortezomib I C NCT00791011
Lung 172 Paclitaxel,Carboplatin I/II C NCT00534027
Ovarian,Peritoneal,FalopianTube 27 Birinapant I C NCT01940172
Pancreatic ND Capecitabine,Gemcitabine,Hydrochloride,Radiation I/II W NCT01017822
Pancreatic,Adenocarcinoma 138 AMG479,Placebo I/II C NCT00630552
Sarcoma 134 Placebo,Doxorubicin I/II C NCT00626704
AMG951(rhAPO2L/TRAIL)
Lung 213 Bevacizumab,Carboplatin,Paclitaxel II C NCT00508625
Tigatuzumab(CS-1008)
Breast 66 Abraxane II A(nr) NCT01307891
Colon 19 Differentvariantsoftigatuzumabantibody I C NCT01220999
Colon 21 FOLFIRI I C NCT01124630
Colon 8 Irinotecan II T NCT00969033
Liver,Hepatic 172 Sorafenib II C NCT01033240
Lung 109 Paclitaxel,Carboplatin,Placebo II C NCT00991796
Lymphoma 40 alone I C NCT00320827
Ovarian 24 Paclitaxel,Carboplatin II C NCT00945191
Pancreatic 65 Gemcitabine II C NCT00521404
Dulanermin
Colon 23 Bevacizumab,FOLFOX I C NCT00873756
Colon 42 FOLFIRI,Bevacizumab,Cetuximab,Irinotecan I C NCT00671372
NHL 72 Rituximab I/II T NCT00400764
Lexatumumab
Sarcoma,Neuroblastoma 19 InterferonGamma1b I T NCT00428272
Mapatumumab(HGS-ETR1)
Carcinoma,Hepatocellular 23 Sorafenib I C NCT00712855
Carcinoma,Hepatocellular 101 Placebo,Sorafenib II A(nr) NCT01258608
Cervical 9 Cisplatin,Radiotherapy I/II C NCT01088347
Lung 111 Paclitaxel,Carboplatin II C NCT00583830
MultipleMyeoloma 105 Bortezomib II C NCT00315757
Drozitumab(PRO95780)
Chondrosarcoma 90 Alone-Nocombinations II T NCT00543712
Colon 20 Bevacizumab,Cetuximab,FOLFIRI,Irinotecan I C NCT00497497
Colon 9 Bevacizumab,FOLFOX I C NCT00851136
Lung 128 Bevacizumab,Carboplatin,Paclitaxel,Placebo II C NCT00480831
NHL 49 Rituximab II C NCT00517049
TAS266(TetravalentNanobody)
AdvancedSolidTumor 6 Alone-Nocombinations I T NCT01529307
TRAIL-R1Mab
Lung,Carcinoma ND Alone-Nocombinations II C NCT00092924
NHL ND Alone-Nocombinations II C NCT00094848
NHL:non-Hodgkinlymphoma;C:Completed,A:Active;T:terminated;W:Withdrawn;Mab:monoclonalantibody;nr:notrecruiting;n:numberofpatientsenrolled;ND: numberofpatientsenrollednotdeclared.
for DR-induced chemokines, introducing theconcept that cells dyingbypro-apoptotic signalsmediated byFas,TNF andTRAIL are notimmunologically silentand mayrelease factors ableto coordinatetheremovalofdyingcellsbyphagocytes(Cullenetal.,
2013).Theauthorsreportedinparticulartheactivationofa
pro-inflammatoryprogram,uncoupledfromcaspasesactivityandcell
death,thatresultsinthesecretionofanarrayofchemokinesand
cytokinestriggeringchemotaxistowarddyingcells.Their
discov-erysuggestedasortof“find-me”signaloriginatingfromapoptotic
cellsandshowedforthefirsttimetheDR-inducedcelldeathasan
immunologicallyactiveprocess.
ItbecomesclearthattheroleofTRAILiscomplexand
multi-facetedalsointhecontextofcancer,andtheclassificationofTRAIL
andFasreceptorsas“deathreceptors”appearsasan
oversimplifica-tionsincetheiractivationisnotmerelycellapoptosisinductionbut
alsocytokines/chemokinesproductionandcontrolofcellfunctions
suchasproliferation,migrationand differentiation.Totakeinto
accountthiscomplexityisthereforemandatoryduringthedesign
ofnewanticancertherapiesbasedonTRAILincombinationwith
synergisticagents,inparticulartoavoidpro-tumoralsideeffectsin
thecaseofTRAIL-resistanttumors.Moreover,ithastobeconsider
thatrecentliteraturehasshownthatthemajorityof
intracellu-larmechanismsofTRAILresistanceimplicatesdisturbanceofthe
oxidativestress“homeostasis”.
2.2.3. TRAILandROSincancer
Looking for intracellular targetsthat might helpTRAIL
anti-canceractivity,thereisgrowinginterestintheinterplaybetween
TRAIL-mediatedsignalingandoxidativestressresponses.Thelink
betweenoxidativestressandcancerisnotarecentdiscovery,but
thecrosstalkwiththeTRAILpathwayhasamorerecentorigin.
Fig.2.RedoxsignalingandTRAILbiologicalactivity.ThepictureshowssomeofthemolecularmediatorsofthecrosstalkbetweenredoxsignalingandTRAILbiological activity.NOisnitricoxide;ROSarereactiveoxygenspecies;ASMisacidsphingomyelinase;SODissuperoxidedismutase;ERisendoplasmicreticulum;GSRisglutathione reductase;DRsaredeathreceptors;NOXareNADPHoxidases;O2−issuperoxide;H2O2ishydrogenperoxide;ONOO−isperoxynitrite.
tocaspasescascadeafterTRAILtreatmentweremadebyourgroup
inleukemiccells(Secchieroetal.,2001)andTRAILandROSwere
investigatedbyothergroupsindifferentpreclinicalmodelsofsolid
cancer.Forexample,ithasdemonstratedthatERstress/ROS(H2O2
andO2−)inductioncanresultintheupregulationofDR5inhuman
carcinomacelllines(YamaguchiandWang,2004)and,associated
tothedownregulationofsurvivin,in TRAIL-resistantmelanoma
cells(Tseetal.,2014).Moreover,regulationofDR4andDR5
expres-sionhasbeenassociatedtoER-mediatedapoptosisinhumanlung
cancercells treatedwithER stressinducing agents (DDIT3 and
KAT2A)(Lietal.,2015).SeveralotherreportsindicatethatTRAIL
receptorsDR4andDR5canbeinducedbyERstress,suggesting
thatERstressordrugs,suchasthapsigargin,canbeusedto
sensi-tizedcellstoTRAIL-mediatedapoptosis(IurlaroandMunoz-Pinedo,
2016).
Otherstudies describe a different mechanism of interaction
betweenTRAILandredoxsignalingviacellmembrane
depolariza-tion,duetoimpairmentofionchannelsortransportersofNa+,K+,
Cl−andCa2+,andtodisruptionofintracellularionhomeostasis,
leadingtoapoptosis.Severalhumanmalignanttumorcells
(includ-ingmelanoma,leukemiaand lungcancer),but notnormal cells,
showrobustandpersistentdepolarizationafterTRAILtreatment
inadoseandtime-dependentmannerandincorrelationwiththe
specificcellsensitivitytoTRAIL-inducedapoptosis(Suzukietal.,
2012; Inoue and Suzuki-Karasaki, 2013; Suzuki-Karasaki et al., 2014a).Thistypeofdepolarizationhasbeendescribedasanearly
andpro-apoptoticeventinducedalsobyotherpro-apoptoticwell
definedagentssuchasFas,rotenoneandarsenictrioxide(Bortner
etal.,2001;Nolteetal.,2004;Yinetal.,2009),anditis
associ-atedwithactivationofthemitochondrialapoptoticpathwayand
ROSgeneration.Inthisline,theresultsreportedbySuzuki-karasaki
(Suzuki-Karasakietal.,2014a)suggesttheexistenceofapositive
loopbetweendepolarizationandmitochondrial-derivedROS(O2−)
accumulationthroughDR5expression,althoughthespecific
mech-anismofmodulationandtheroleofNa+-K−ATPasestillneedtobe
definedinthecontextofTRAIL-inducedapoptosis.Inthisregard,a
varietyofcompoundscapableoffurtherincreasetheintracellular
levelsofROSinducedbyTRAIL,inparticularH2O2,hasbeenshown
tohavethecapabilitytopotentiatetheTRAILantitumoralefficacy
inseveraltumormodels(Suzuki-Karasakietal.,2014a,b)andoffers
increasingopportunityoftherapy.Ofinterest,alsoseveralnatural
pharmacologicalagentshaveshownthepotentialtosensitize
can-cercells toTRAILapoptotic activityviaROSproductionandthe
evidencethattheyareabletoupregulateTRAIL-DRsmakesthem
anappealingtherapeuticoptiontobeexploredalsoatthe
clini-callevelincombinationwithrecombinantTRAILorDRs-agonist
antibodies(SupplementaryTable1).Anotherkey componentof
theoxidativestressresponse,theenzymeGlutathionereductase
(GSR),hasbeenshowntobeinvolvedintheTRAIL-mediated
apo-ptosisin melanomaand carcinomacelllines ofdifferentorigin
(prostate,pancreatic,lungandbreast).Inthissetting,new
com-pounds,identifiedbyhighthroughputscreeningandabletoinhibit
theactivityofGSR,withaconcomitantdropofintracellular
antiox-idantreducedglutathione(GSH)andinductionofoxidativestress,
havebeenshowntopotentiateTRAILtoxicityinvitroandinmouse
xenograftmodels(Rozanovetal.,2015),offeringanotherweapon
tosupportTRAILanticancerskills.
TheinterplaybetweenoxidativestressandTRAIL-induced
apo-ptosis hasbeen alsoreported for specificNO-derived chemical
species,referringinparticulartoperoxynitrite,ahighlyreactive
freeradicalresultingfromtherapidinteractionbetweenNOand
superoxide(Stamler etal.,1992).Oncegenerated,peroxynitrite
actsasapotentoxidantabletotriggerawiderangeofeffects
culmi-natingincelldysfunction,apoptosisornecrosis(Viragetal.,2003)
andithasbeensuggestedtobeabletopotentiateTRAIL-induced
apoptoticdeath(Leeetal.,2001).Inaddition,inarecentworkSeah
andcolleagueshavehighlightedtheroleofperoxynitritein
medi-ating the TRAIL-mediated apoptotic effect in cisplatin-resistant
cancercells(Seahetal.,2015).Inlinewithpreviousfindings,the
authorsdetectedmitochondrialdefectsoncisplatin-resistantlung
andovariancancercellscomparedtowildtype(cancer)cellsand
reporteda higher susceptibilityof thesecells toTRAIL-induced
apoptosis.Thiseffectoncisplatin-resistantcellswasinparticular
associatedwithadifferentre-destributionofDRstolipidraftson
theplasmamembrane,increasediNOSexpressionwithsubsequent
NOgenerationbytargetcellshighlightingthekeyroleof
peroxyni-tritethatappearstoberequiredformaximalTRAIL-inducedcell
death.Itisofinterestthatthisstudysuggeststhepresenceofa
iNOSactivityleadingtoNOreleaseandperoxynitriteproduction
thatinturnamplifydeathexecution(Seahetal.,2015).
Overall,thereisincreasingevidencesuggestingthattumorcells
aremoresuitablethannormalcellstooxidativestressand
depolar-izationandmoreexposedtomitochondrialnetworkabnormalities
andthatthisvulnerabilitycanberelevanttothetumor-targeting
killingbyTRAIL.Moreover,consideringthat:i)cancerscan
orig-inatefromchronicallyinflamedtissues(Reuteret al.,2010);ii)
inflammationistightlyregulatedbytheredoxsignaling(Leietal.,
2015)andthatiii)increasingreportshighlighttheroleofTRAIL
signalingin both inflammationand redoxmodulation, there is
growingattention toTRAIL asa key element able totalk with
andmodulateallthesepathways.Thisfeature,togetherwiththe
pro-apoptoticanticancercapabilityofTRAIL,canbetailoredand
guidedfor severalpurposes.In particular,thesynergy between
TRAILandmoleculesabletotargetoneofthementionedpathways
willprovideefficaciouscombinationsabletotargetandkilleven
TRAIL-resistanttumorswhilesavingnormalcells.
3. Concludingremarks
WhileROSwereinitiallyconsideredspeciesresponsibleonlyfor
celldamageandcelldeath,theirrolehasbeennowrevisedinlight
oftheirinvolvementinamorecomplexrangeofreactionsincluding
signaltransductionpathwaysandregulationofseveralcell
func-tions.Theattemptofdefiningthespecifictypeofoxidativestress
ineachphysiopathologicaland/orexperimentalcontext,perhaps
byusingtheproposed“intensity-based”classification(Lushchak,
2014),isstillachallengingtasksincespecificandstrictguidelinesto
discriminatebetweendifferentlevels/rangesofoxidativestressare
needed.InthecontextofTRAIL,thereisgrowinginterestin
under-standinghowreactivespeciesandredoxmediatorscaninterfere
withitspathwaysandmechanismsofactionsincethese
knowl-edgemightbeusedtoimproveandoptimizeitsbiologicalactivity.
ThebindingofTRAILtoitssurfacereceptorsisfarmorethatsimply
caspasesactivationandthemechanismsofprotectionofnormal
cellsagainstapoptosisaswellastheabilityofactivateopposite
pathwaysleadingtodifferentbiologicaloutcomesarenotclearand
needfurtherinsights.Inthislight,theconceptofmembrane
traf-fickingandthedemonstrationofacrosstalkbetweenoxidative
systemandASMpathwayinDR-mediatedsignalingactivationhas
shedsomelightontheregulationofendothelialcellfunctionsand
onTRAIL-inducedeffects(Fig.2).InthecontextofcancerTRAIL
already represents a therapeutic option under evaluation used
eitheraloneorincombinationwithothermolecules,inparticular
withROSinducers,inordertotriggerTRAIL-mediatedapoptosis
(Fig.2).Nonetheless,ithasbeenrecentlyshowedthatmild
oxida-tivestresscontributedtoescape TRAIL-mediated apoptosisand
mediatedTRAILtoleranceinanovariancancermodel(Luetal.,
2016),inagreementwithpreviousfindingsaboutthepromoting
roleofROSinTRAILresistance(Choietal.,2010).These
contradic-toryresults,inlinewiththe“dual”natureofTRAIL,highlightthe
needoffurtherinvestigationstogaindeeperinsightsonthe
mech-anismsofTRAILresistanceand onthequantificationofthereal
intracellularROSconcentrationsinrelationtothemodifications
inducedinROStargetsineach experimental/physiopathological
condition.Furtherinvestigationsarealsorequiredtoclarifyother
issuessuchasthemechanismsofDRrecruitmentandthe
forma-tionofredoxsignalingplatformsuponTRAILstimulationandthe
functions/effectsinducedby“localdoses”oftheTRAILinput.
Finally,newmechanisticcomprehensionsofthelinkbetween
ROSandredoxsignalingwithTRAIL-inducedresponsesinspecific
cellsubsetsindifferentphysiopathologicalcontexts,including
can-cer,willhelptounderstandthe“life-death”signalingmediatedby
TRAIL,withsignificanttherapeuticimplications.
AppendixA. Supplementarydata
Supplementarydataassociatedwiththisarticlecanbefound,
intheonlineversion,athttp://dx.doi.org/10.1016/j.biocel.2016.09.
019.
References
Alladina,S.J.,Song,J.H.,Davidge,S.T.,Hao,C.,Easton,A.S.,2005.TRAIL-induced apoptosisinhumanvascularendotheliumisregulatedbyphosphatidylinositol 3-kinase/AktthroughtheshortformofcellularFLIPandBcl-2.J.Vasc.Res.42, 337–347.
Ashkenazi,A.,Herbst,R.S.,2008.Tokillatumorcell:thepotentialofproapoptotic receptoragonists.J.Clin.Invest.118,1979–1990.
Ashkenazi,A.,Pai,R.C.,Fong,S.,Leung,S.,Lawrence,D.A.,Marsters,S.A.,Blackie,C., Chang,L.,McMurtrey,A.E.,Hebert,A.,DeForge,L.,Koumenis,I.L.,Lewis,D., Harris,L.,Bussiere,J.,Koeppen,H.,Shahrokh,Z.,Schwall,R.H.,1999.Safetyand antitumoractivityofrecombinantsolubleApo2ligand.J.Clin.Invest.104, 155–162.
Audo,R.,Combe,B.,Hahne,M.,Morel,J.,2013.ThetwodirectionsofTNF-related apoptosis-inducingligandinrheumatoidarthritis.Cytokine63,81–90. Baker,S.J.,Reddy,E.P.,1996.Transducersoflifeanddeath:TNFreceptor
superfamilyandassociatedproteins.Oncogene12,1–9.
Bao,J.X.,Xia,M.,Poklis,J.L.,Han,W.Q.,Brimson,C.,Li,P.L.,2010a.Triggeringroleof acidsphingomyelinaseinendotheliallysosome-membranefusionand dysfunctionincoronaryarteries.Am.J.Physiol.HeartCirc.Physiol.298, H992–H1002.
Bao,J.X.,Jin,S.,Zhang,F.,Wang,Z.C.,Li,N.,Li,P.L.,2010b.Activationofmembrane NADPHoxidaseassociatedwithlysosome-targetedacidsphingomyelinasein coronaryendothelialcells.Antioxid.RedoxSignal.12,703–712.
Ben-Neriah,Y.,Karin,M.,2011.Inflammationmeetscancer,withNF-kappaBasthe matchmaker.Nat.Immunol.12,715–723.
Berg,D.,Stuhmer,T.,Siegmund,D.,Muller,N.,Giner,T.,Dittrich-Breiholz,O., Kracht,M.,Bargou,R.,Wajant,H.,2009.Oligomerizedtumornecrosis factor-relatedapoptosisinducingligandstronglyinducescelldeathin myelomacells,butalsoactivatesproinflammatorysignalingpathways.FEBSJ. 276,6912–6927.
Bernardi,S.,Norcio,A.,Toffoli,B.,Zauli,G.,Secchiero,P.,2012a.Potentialroleof TRAILinthemanagementofautoimmunediabetesmellitus.Curr.Pharm.Des. 18,5759–5765.
Bernardi,S.,Zauli,G.,Tikellis,C.,Candido,R.,Fabris,B.,Secchiero,P.,Cooper,M.E., Thomas,M.C.,2012b.TNF-relatedapoptosis-inducingligandsignificantly attenuatesmetabolicabnormalitiesinhigh-fat-fedmicereducingadiposity andsystemicinflammation.Clin.Sci.123,547–555.
Bisgin,A.,Yalcin,A.D.,Gorczynski,R.M.,2012.Circulatingsolubletumornecrosis factorrelatedapoptosisinducing-ligand(TRAIL)isdecreasedintype-2newly diagnosed,non-drugusingdiabeticpatients.DiabetesRes.Clin.Pract.96, e84–86.
Bonnefont-Rousselot,D.,2002.Glucoseandreactiveoxygenspecies.Curr.Opin. Clin.Nutr.Metab.Care5,561–568.
Bortner,C.D.,Gomez-Angelats,M.,Cidlowski,J.A.,2001.Plasmamembrane depolarizationwithoutrepolarizationisanearlymoleculareventin anti-Fas-inducedapoptosis.J.Biol.Chem.276,4304–4314.
Bossi,F.,Bernardi,S.,Zauli,G.,Secchiero,P.,Fabris,B.,2015.TRAILmodulatesthe immunesystemandprotectsagainstthedevelopmentofdiabetes.J.Immunol. Res.2015,680749.
Brombo,G.,Volpato,S.,Secchiero,P.,Passaro,A.,Bosi,C.,Zuliani,G.,Zauli,G.,2013. Associationofsolubletumornecrosisfactor-relatedapoptosis-inducingligand (TRAIL)withcentraladiposityandlow-densitylipoproteincholesterol.PLoS One8,e58225.
Buneker,C.,Mohr,A.,Zwacka,R.M.,2009.TheTRAIL-receptor-1:TRAIL-receptor-3 and-4ratioisapredictorforTRAILsensitivityofcancercells.Oncol.Rep.21, 1289–1295.
Cai,H.,Harrison,D.G.,2000.Endothelialdysfunctionincardiovasculardiseases: theroleofoxidantstress.Circ.Res.87,840–844.
Cantarella,G.,DiBenedetto,G.,Ribatti,D.,Saccani-Jotti,G.,Bernardini,R.,2014. Involvementofcaspase8andc-FLIPLintheproangiogeniceffectsofthe tumournecrosisfactor-relatedapoptosis-inducingligand(TRAIL).FEBSJ.281, 1505–1513.
Chen,L.,Park,S.M.,Tumanov,A.V.,Hau,A.,Sawada,K.,Feig,C.,Turner,J.R.,Fu,Y.X., Romero,I.L.,Lengyel,E.,Peter,M.E.,2010.CD95promotestumourgrowth. Nature465,492–496.
Chen,D.,Yu,J.,Zhang,L.,2016.Necroptosis:analternativecelldeathprogram defendingagainstcancer.Biochim.Biophys.Acta1865,228–236. Cheng,W.,Zhao,Y.,Wang,S.,Jiang,F.,2014.Tumornecrosisfactor-related
apoptosis-inducingligandinvascularinflammationandatherosclerosis:a protectororculprit.Vascul.Pharmacol.63,135–144.
Choi,K.,Ryu,S.W.,Song,S.,Choi,H.,Kang,S.W.,Choi,C.,2010.Caspase-dependent generationofreactiveoxygenspeciesinhumanastrocytomacellscontributes toresistancetoTRAIL-mediatedapoptosis.CellDeathDiffer.17,833–845. Collison,A.,Li,J.,PereiradeSiqueira,A.,Zhang,J.,Toop,H.D.,Morris,J.C.,Foster,
P.S.,Mattes,J.,2014.Tumornecrosisfactor-relatedapoptosis-inducingligand regulateshallmarkfeaturesofairwaysremodelinginallergicairwaysdisease. Am.J.Respir.CellMol.Biol.51,86–93.
Cullen,S.P.,Martin,S.J.,2015.FasandTRAIL‘deathreceptors’asinitiatorsof inflammation:implicationsforcancer.Semin.CellDev.Biol.39,26–34. Cullen,S.P.,Henry,C.M.,Kearney,C.J.,Logue,S.E.,Feoktistova,M.,Tynan,G.A.,
Lavelle,E.C.,Leverkus,M.,Martin,S.J.,2013.Fas/CD95-inducedchemokines canserveasfind-mesignalsforapoptoticcells.Mol.Cell49,1034–1048. Delmas,D.,Rebe,C.,Micheau,O.,Athias,A.,Gambert,P.,Grazide,S.,Laurent,G.,
Latruffe,N.,Solary,E.,2004.RedistributionofCD95,DR4andDR5inrafts accountsforthesynergistictoxicityofresveratrolanddeathreceptorligands incoloncarcinomacells.Oncogene23,8979–8986.
DiBartolo,B.A.,Chan,J.,Bennett,M.R.,Cartland,S.,Bao,S.,Tuch,B.E.,Kavurma, M.M.,2011.TNF-relatedapoptosis-inducingligand(TRAIL)protectsagainst diabetesandatherosclerosisinApoe(−)/(−)mice.Diabetologia54,3157–3167. DiBartolo,B.A.,Cartland,S.P.,Prado-Lourenco,L.,Griffith,T.S.,Gentile,C.,
Ravindran,J.,Azahri,N.S.,Thai,T.,Yeung,A.W.,Thomas,S.R.,Kavurma,M.M., 2015.Tumornecrosisfactor-Relatedapoptosis-inducingligand(TRAIL) promotesangiogenesisandischemia-inducedneovascularizationviaNADPH oxidase4(NOX4)andnitricoxide-dependentmechanisms.J.Am.HeartAssoc., 4.
DiPietro,R.,Zauli,G.,2004.Emergingnon-apoptoticfunctionsoftumornecrosis factor-relatedapoptosis-inducingligand(TRAIL)/Apo2L.J.Cell.Physiol.201, 331–340.
Dimmeler,S.,Zeiher,A.M.,1999.Nitricoxide-anendothelialcellsurvivalfactor. CellDeathDiffer.6,964–968.
Dimmeler,S.,Fleming,I.,Fisslthaler,B.,Hermann,C.,Busse,R.,Zeiher,A.M.,1999. ActivationofnitricoxidesynthaseinendothelialcellsbyAkt-dependent phosphorylation.Nature399,601–605.
Droge,W.,2002.Freeradicalsinthephysiologicalcontrolofcellfunction.Physiol. Rev.82,47–95.
Dumitru,C.A.,Gulbins,E.,2006.TRAILactivatesacidsphingomyelinaseviaaredox mechanismandreleasesceramidetotriggerapoptosis.Oncogene25, 5612–5625.
Falschlehner,C.,Emmerich,C.H.,Gerlach,B.,Walczak,H.,2007.TRAILsignalling: decisionsbetweenlifeanddeath.Int.J.Biochem.CellBiol.39,1462–1475. Falschlehner,C.,Ganten,T.M.,Koschny,R.,Schaefer,U.,Walczak,H.,2009.TRAIL
andotherTRAILreceptoragonistsasnovelcancertherapeutics.Adv.Exp.Med. Biol.647,195–206.
Farooqi,A.A.,Li,K.T.,Fayyaz,S.,Chang,Y.T.,Ismail,M.,Liaw,C.C.,Yuan,S.S.,Tang, J.Y.,Chang,H.W.,2015.Anticancerdrugsforthemodulationofendoplasmic reticulumstressandoxidativestress.TumourBiol.36,5743–5752. Fisslthaler,B.,Dimmeler,S.,Hermann,C.,Busse,R.,Fleming,I.,2000.
Phosphorylationandactivationoftheendothelialnitricoxidesynthasebyfluid shearstress.ActaPhysiol.Scand.168,81–88.
Forde,H.,Harper,E.,Davenport,C.,Rochfort,K.D.,Wallace,R.,Murphy,R.P.,Smith, D.,Cummins,P.M.,2016.Thebeneficialpleiotropiceffectsoftumournecrosis factor-relatedapoptosis-inducingligand(TRAIL)withinthevasculature:a reviewoftheevidence.Atherosclerosis247,87–96.
Fossati,S.,Ghiso,J.,Rostagno,A.,2012.TRAILdeathreceptorsDR4andDR5 mediatecerebralmicrovascularendothelialcellapoptosisinducedby oligomericAlzheimer’sAbeta.CellDeathDis.3,e321.
Fuchs,Y.,Steller,H.,2015.Livetodieanotherway:modesofprogrammedcell deathandthesignalsemanatingfromdyingcells.Nat.Rev.Mol.CellBiol.16, 329–344.
Gasparini,C.,VecchiBrumatti,L.,Monasta,L.,Zauli,G.,2013.TRAIL-based therapeuticapproachesforthetreatmentofpediatricmalignancies.Curr.Med. Chem.20,2254–2271.
Gochuico,B.R.,Zhang,J.,Ma,B.Y.,Marshak-Rothstein,A.,2000.FineA:TRAIL expressioninvascularsmoothmuscle.Am.J.Physiol.LungCell.Mol.Physiol. 278,L1045–1050.
Harper,E.,Forde,H.,Davenport,C.,Rochfort,K.D.,Smith,D.,Cummins,P.M.,2016. Vascularcalcificationintype-2diabetesandcardiovasculardisease:integrative rolesforOPG,RANKLandTRAIL.Vascul.Pharmacol.82(July),30–40. Hayakawa,Y.,Screpanti,V.,Yagita,H.,Grandien,A.,Ljunggren,H.G.,Smyth,M.J.,
Chambers,B.J.,2004.NKcellTRAILeliminatesimmaturedendriticcellsinvivo andlimitsdendriticcellvaccinationefficacy.J.Immunol.172,123–129. Higashi,Y.,Maruhashi,T.,Noma,K.,Kihara,Y.,2014.Oxidativestressand
endothelialdysfunction:clinicalevidenceandtherapeuticimplications. TrendsCardiovasc.Med.24,165–169.
Holoch,P.A.,Griffith,T.S.,2009.TNF-relatedapoptosis-inducingligand(TRAIL):a newpathtoanti-cancertherapies.Eur.J.Pharmacol.625,63–72.
Inoue,T.,Suzuki-Karasaki,Y.,2013.Mitochondrialsuperoxidemediates mitochondrialandendoplasmicreticulumdysfunctionsinTRAIL-induced apoptosisinJurkatcells.FreeRadic.Biol.Med.61,273–284.
Ishimura,N.,Isomoto,H.,Bronk,S.F.,Gores,G.J.,2006.Trailinducescellmigration andinvasioninapoptosis-resistantcholangiocarcinomacells.Am.J.Physiol. Gastrointest.LiverPhysiol.290,G129–136.
Iurlaro,R.,Munoz-Pinedo,C.,2016.Celldeathinducedbyendoplasmicreticulum stress.FEBSJ.283(July(14)),2640–2652.
Janssen,E.M.,Droin,N.M.,Lemmens,E.E.,Pinkoski,M.J.,Bensinger,S.J.,Ehst,B.D., Griffith,T.S.,Green,D.R.,Schoenberger,S.P.,2005.CD4+T-cellhelpcontrols CD8+T-cellmemoryviaTRAIL-mediatedactivation-inducedcelldeath.Nature 434,88–93.
Jin,S.,Yi,F.,Zhang,F.,Poklis,J.L.,Li,P.L.,2008.Lysosomaltargetingandtrafficking ofacidsphingomyelinasetolipidraftplatformsincoronaryendothelialcells. Arterioscler.Thromb.Vasc.Biol.28,2056–2062.
Jin,S.,Zhou,F.,Katirai,F.,Li,P.L.,2011.Lipidraftredoxsignaling:molecular mechanismsinhealthanddisease.Antioxid.RedoxSignal.15,1043–1083.
Jouan-Lanhouet,S.,Arshad,M.I.,Piquet-Pellorce,C.,Martin-Chouly,C.,Le Moigne-Muller,G.,VanHerreweghe,F.,Takahashi,N.,Sergent,O.,
Lagadic-Gossmann,D.,Vandenabeele,P.,Samson,M.,Dimanche-Boitrel,M.T., 2012.TRAILinducesnecroptosisinvolvingRIPK1/RIPK3-dependentPARP-1 activation.CellDeathDiffer.19,2003–2014.
Lassegue,B.,Griendling,K.K.,2010.NADPHoxidases:functionsandpathologiesin thevasculature.Arterioscler.Thromb.Vasc.Biol.30,653–661.
Lee,Y.J.,Lee,K.H.,Kim,H.R.,Jessup,J.M.,Seol,D.W.,Kim,T.H.,Billiar,T.R.,Song, Y.K.,2001.SodiumnitroprussideenhancesTRAIL-inducedapoptosisviaa mitochondria-dependentpathwayinhumancolorectalcarcinomaCX-1cells. Oncogene20,1476–1485.
Lei,Y.,Wang,K.,Deng,L.,Chen,Y.,Nice,E.C.,Huang,C.,2015.Redoxregulationof inflammation:oldelements,anewstory.Med.Res.Rev.35,306–340. Lemke,J.,vonKarstedt,S.,Zinngrebe,J.,Walczak,H.,2014.GettingTRAILbackon
trackforcancertherapy.CellDeathDiffer.21,1350–1364.
Li,J.H.,Kirkiles-Smith,N.C.,McNiff,J.M.,Pober,J.S.,2003.TRAILinducesapoptosis andinflammatorygeneexpressioninhumanendothelialcells.J.Immunol. 171,1526–1533.
Li,X.,Becker,K.A.,Zhang,Y.,2010.Ceramideinredoxsignalingandcardiovascular diseases.Cell.Physiol.Biochem.26,41–48.
Li,X.,Han,W.Q.,Boini,K.M.,Xia,M.,Zhang,Y.,Li,P.L.,2013.TRAILdeathreceptor4 signalingvialysosomefusionandmembraneraftclusteringincoronary arterialendothelialcells:evidencefromASMknockoutmice.J.Mol.Med.91, 25–36.
Li,T.,Su,L.,Lei,Y.,Liu,X.,Zhang,Y.,Liu,X.,2015.DDIT3andKAT2Aproteins regulateTNFRSF10AandTNFRSF10Bexpressioninendoplasmicreticulum stress-mediatedapoptosisinhumanlungcancercells.J.Biol.Chem.290, 11108–11118.
Liabakk,N.B.,Sundan,A.,Torp,S.,Aukrust,P.,Froland,S.S.,Espevik,T.,2002. Development,characterizationanduseofmonoclonalantibodiesagainst sTRAIL:measurementofsTRAILbyELISA.J.Immunol.Methods259, 119–128.
Liabeuf,S.,Barreto,D.V.,Barreto,F.C.,Chasseraud,M.,Brazier,M.,Choukroun,G., Kamel,S.,Massy,Z.A.,2010.ThecirculatingsolubleTRAILisanegativemarker forinflammationinverselyassociatedwiththemortalityriskinchronickidney diseasepatients.Nephrol.Dial.Transplant.25,2596–2602.
Liu,M.,Xiang,G.,Lu,J.,Xiang,L.,Dong,J.,Mei,W.,2014.TRAILprotectsagainst endotheliuminjuryindiabetesviaAkt-eNOSsignaling.Atherosclerosis237, 718–724.
Lu,J.,Zhang,L.,Xie,F.,Zhu,L.,Li,X.,Ouyang,J.,He,X.,Han,S.,Yi,C.,2016.Mild oxidativestressinducedbyalowdoseofcisplatincontributestotheescapeof TRAIL-mediatedapoptosisintheovariancancerSKOV3cellline.Oncol.Rep. 35,3427–3434.
Lushchak,V.I.,2014.Freeradicals,reactiveoxygenspecies,oxidativestressandits classification.Chem.Biol.Interact.224,164–175.
Michowitz,Y.,Goldstein,E.,Roth,A.,Afek,A.,Abashidze,A.,BenGal,Y.,Keren,G., George,J.,2005.Theinvolvementoftumornecrosisfactor-related
apoptosis-inducingligand(TRAIL)inatherosclerosis.J.Am.Coll.Cardiol.45, 1018–1024.
deMiguel,D.,Lemke,J.,Anel,A.,Walczak,H.,Martinez-Lostao,L.,2016.Onto betterTRAILsforcancertreatment.CellDeathDiffer.23,733–747. Moncada,S.,Palmer,R.M.,Higgs,E.A.,1991.Nitricoxide:physiology,
pathophysiology,andpharmacology.Pharmacol.Rev.43,109–142. Montezano,A.C.,Touyz,R.M.,2012a.Oxidativestress,Noxs,andhypertension:
experimentalevidenceandclinicalcontroversies.Ann.Med.44(Suppl.1), S2–16.
Montezano,A.C.,Touyz,R.M.,2012b.Reactiveoxygenspeciesandendothelial function-roleofnitricoxidesynthaseuncouplingandNoxfamilynicotinamide adeninedinucleotidephosphateoxidases.BasicClin.Pharmacol.Toxicol.110, 87–94.
Nakagami,H.,Kaneda,Y.,Ogihara,T.,Morishita,R.,2005.Endothelialdysfunction inhyperglycemiaasatriggerofatherosclerosis.Curr.DiabetesRev.1,59–63. Nesterov,A.,Ivashchenko,Y.,Kraft,A.S.,2002.Tumornecrosisfactor-related
apoptosis-inducingligand(TRAIL)triggersapoptosisinnormalprostate epithelialcells.Oncogene21,1135–1140.
Niessner,A.,Hohensinner,P.J.,Rychli,K.,Neuhold,S.,Zorn,G.,Richter,B., Hulsmann,M.,Berger,R.,Mortl,D.,Huber,K.,Wojta,J.,Pacher,R.,2009. Prognosticvalueofapoptosismarkersinadvancedheartfailurepatients.Eur. HeartJ.30,789–796.
Nolte,F.,Friedrich,O.,Rojewski,M.,Fink,R.H.,Schrezenmeier,H.,Korper,S.,2004. Depolarisationoftheplasmamembraneinthearsenictrioxide(As2O3)-and
anti-CD95-inducedapoptosisinmyeloidcells.FEBSLett.578,85–89. O’Brien,L.A.,Richardson,M.A.,Mehrbod,S.F.,Berg,D.T.,Gerlitz,B.,Gupta,A.,
Grinnell,B.W.,2007.ActivatedproteinCdecreasestumornecrosisfactor relatedapoptosis-inducingligandbyanEPCR-independentmechanism involvingEgr-1/Erk-1/2activation.Arterioscler.Thromb.Vasc.Biol.27, 2634–2641.
Orlinick,J.R.,Chao,M.V.,1998.TNF-relatedligandsandtheirreceptors.Cell.Signal. 10,543–551.
Osmancik,P.,Teringova,E.,Tousek,P.,Paulu,P.,Widimsky,P.,2013.Prognostic valueofTNF-relatedapoptosisinducingligand(TRAIL)inacutecoronary syndromepatients.PLoSOne8,e53860.
Panieri,E.,Santoro,M.M.,2016.ROShomeostasisandmetabolism:adangerous liasonincancercells.CellDeath.Dis.7,e2253.
Park,K.J.,Lee,C.H.,Kim,A.,Jeong,K.J.,Kim,C.H.,Kim,Y.S.,2012.Deathreceptors4 and5activateNox1NADPHoxidasethroughriboflavinkinasetoinduce
reactiveoxygenspecies-mediatedapoptoticcelldeath.J.Biol.Chem.287, 3313–3325.
Pitti,R.M.,Marsters,S.A.,Ruppert,S.,Donahue,C.J.,Moore,A.,Ashkenazi,A.,1996. InductionofapoptosisbyApo-2ligand,anewmemberofthetumornecrosis factorcytokinefamily.J.Biol.Chem.271,12687–12690.
Pritzker,L.B.,Scatena,M.,Giachelli,C.M.,2004.Theroleofosteoprotegerinand tumornecrosisfactor-relatedapoptosis-inducingligandinhuman microvascularendothelialcellsurvival.Mol.Biol.Cell15,2834–2841. Raaz,U.,Toh,R.,Maegdefessel,L.,Adam,M.,Nakagami,F.,Emrich,F.C.,Spin,J.M.,
Tsao,P.S.,2014.Hemodynamicregulationofreactiveoxygenspecies: implicationsforvasculardiseases.Antioxid.RedoxSignal.20,914–928. Reuter,S.,Gupta,S.C.,Chaturvedi,M.M.,Aggarwal,B.B.,2010.Oxidativestress,
inflammation,andcancer:howaretheylinked?FreeRadic.Biol.Med.49, 1603–1616.
Ross,R.,1999.Atherosclerosisisaninflammatorydisease.Am.HeartJ.138, S419–420.
Rozanov,D.,Cheltsov,A.,Sergienko,E.,Vasile,S.,Golubkov,V.,Aleshin,A.E.,Levin, T.,Traer,E.,Hann,B.,Freimuth,J.,Alexeev,N.,Alekseyev,M.A.,Budko,S.P., Bachinger,H.P.,Spellman,P.,2015.TRAIL-basedhighthroughputscreening revealsalinkbetweenTRAIL-mediatedapoptosisandglutathionereductase,a keycomponentofoxidativestressresponse.PLoSOne10,e0129566. Schieber,M.,Chandel,N.S.,2014.ROSfunctioninredoxsignalingandoxidative
stress.Curr.Biol.24,R453–462.
Seah,S.,Low,I.C.,Hirpara,J.L.,Sachaphibulkij,K.,Kroemer,G.,Brenner,C.,Pervaiz, S.,2015.Activationofsurrogatedeathreceptorsignalingtriggers
peroxynitrite-dependentexecutionofcisplatin-resistantcancercells.Cell DeathDis.6,e1926.
Secchiero,P.,Zauli,G.,2012.TRAIL,anewweaponagainstneointimalhyperplasia. Cardiology123,94–96.
Secchiero,P.,Gonelli,A.,Celeghini,C.,Mirandola,P.,Guidotti,L.,Visani,G., Capitani,S.,Zauli,G.,2001.Activationofthenitricoxidesynthasepathway representsakeycomponentoftumornecrosisfactor-related
apoptosis-inducingligand-mediatedcytotoxicityonhematologic malignancies.Blood98,2220–2228.
Secchiero,P.,Gonelli,A.,Carnevale,E.,Milani,D.,Pandolfi,A.,Zella,D.,Zauli,G., 2003.TRAILpromotesthesurvivalandproliferationofprimaryhuman vascularendothelialcellsbyactivatingtheAktandERKpathways.Circulation 107,2250–2256.
Secchiero,P.,Corallini,F.,diIasio,M.G.,Gonelli,A.,Barbarotto,E.,Zauli,G.,2005. TRAILcounteractstheproadhesiveactivityofinflammatorycytokinesin endothelialcellsbydown-modulatingCCL8andCXCL10chemokine expressionandrelease.Blood105,3413–3419.
Secchiero,P.,Corallini,F.,Ceconi,C.,Parrinello,G.,Volpato,S.,Ferrari,R.,Zauli,G., 2009.PotentialprognosticsignificanceofdecreasedserumlevelsofTRAILafter acutemyocardialinfarction.PLoSOne4,e4442.
Secchiero,P.,Corallini,F.,Beltrami,A.P.,Ceconi,C.,Bonasia,V.,DiChiara,A.,Ferrari, R.,Zauli,G.,2010a.AnimbalancedOPG/TRAILratioisassociatedtosevere acutemyocardialinfarction.Atherosclerosis210,274–277.
Secchiero,P.,Gonelli,A.,Corallini,F.,Ceconi,C.,Ferrari,R.,Zauli,G.,2010b. Metalloproteinase2cleavesinvitrorecombinantTRAIL:potentialimplications forthedecreasedserumlevelsofTRAILafteracutemyocardialinfarction. Atherosclerosis211,333–336.
Secchiero,P.,Rimondi,E.,diIasio,M.G.,Agnoletto,C.,Melloni,E.,Volpi,I.,Zauli,G., 2013.C-ReactiveproteindownregulatesTRAILexpressioninhumanperipheral monocytesviaanEgr-1-dependentpathway.Clin.CancerRes.19,1949–1959. Sessler,T.,Healy,S.,Samali,A.,Szegezdi,E.,2013.StructuraldeterminantsofDISC
function:newinsightsintodeathreceptor-mediatedapoptosissignalling. Pharmacol.Ther.140,186–199.
Siegmund,D.,Wicovsky,A.,Schmitz,I.,Schulze-Osthoff,K.,Kreuz,S.,Leverkus,M., Dittrich-Breiholz,O.,Kracht,M.,Wajant,H.,2005.Deathreceptor-induced signalingpathwaysaredifferentiallyregulatedbygammainterferonupstream ofcaspase8processing.Mol.Cell.Biol.25,6363–6379.
Sies,H.,1997.Oxidativestress:oxidantsandantioxidants.Exp.Physiol.82, 291–295.
Sies,H.,2015.Oxidativestress:aconceptinredoxbiologyandmedicine.Redox Biol.4,180–183.
Siti,H.N.,Kamisah,Y.,Kamsiah,J.,2015.Theroleofoxidativestress,antioxidants andvascularinflammationincardiovasculardisease(areview).Vascul. Pharmacol.71,40–56.
Stamler,J.S.,Singel,D.J.,Loscalzo,J.,1992.Biochemistryofnitricoxideandits redox-activatedforms.Science258,1898–1902.
Stuckey,D.W.,Shah,K.,2013.TRAILontrial:preclinicaladvancesincancer therapy.TrendsMol.Med.19,685–694.
Suzuki,Y.,Inoue,T.,Murai,M.,Suzuki-Karasaki,M.,Ochiai,T.,Ra,C.,2012. DepolarizationpotentiatesTRAIL-inducedapoptosisinhumanmelanoma cells:roleforATP-sensitiveK+channelsandendoplasmicreticulumstress.Int. J.Oncol.41,465–475.
Suzuki-Karasaki,M.,Ochiai,T.,Suzuki-Karasaki,Y.,2014a.Crosstalkbetween mitochondrialROSanddepolarizationinthepotentiationofTRAIL-induced apoptosisinhumantumorcells.Int.J.Oncol.44,616–628.
Suzuki-Karasaki,Y.,Suzuki-Karasaki,M.,Uchida,M.,Ochiai,T.,2014b. DepolarizationcontrolsTRAIL-sensitizationandtumor-selectivekillingof cancercells:crosstalkwithROS.Front.Oncol.4,128.
Takahashi,K.,Takeda,K.,Saiki,I.,Irimura,T.,Hayakawa,Y.,2013.Functionalroles oftumornecrosisfactor-relatedapoptosis-inducingligand-DR5interactionin
B16F10cellsbyactivatingthenuclearfactor-kappaBpathwaytoinduce metastaticpotential.CancerSci.104,558–562.
Tisato,V.,Secchiero,P.,Rimondi,E.,Gianesini,S.,Menegatti,E.,Casciano,F., Zamboni,P.,Zauli,G.,2013.GM-CSFexhibitsanti-inflammatoryactivityon endothelialcellsderivedfromchronicvenousdiseasepatients.Mediators Inflamm.2013,561689.
Tisato,V.,Garrovo,C.,Biffi,S.,Petrera,F.,Voltan,R.,Casciano,F.,Meroni,G., Agnoletto,C.,Zauli,G.,Secchiero,P.,2014.Intranasaladministrationof recombinantTRAILdown-regulatesCXCL-1/KCinanovalbumin-induced airwayinflammationmurinemodel.PLoSOne9,e115387.
Tisato,V.,Gonelli,A.,Voltan,R.,Secchiero,P.,Zauli,G.,2016.Clinicalperspectives ofTRAIL:insightsintocentralnervoussystemdisorders.Cell.Mol.LifeSci.73, 2017–2027.
Tornese,G.,Iafusco,D.,Monasta,L.,Agnoletto,C.,Tisato,V.,Ventura,A.,Zauli,G., Secchiero,P.,2014.ThelevelsofcirculatingTRAILattheonsetoftype1 diabetesaremarkedlydecreasedinpatientswithketoacidosisandwiththe highestinsulinrequirement.ActaDiabetol.51,239–246.
Tornese,G.,Tisato,V.,Monasta,L.,VecchiBrumatti,L.,Zauli,G.,Secchiero,P.,2015. SerumTRAILlevelsincreaseshortlyafterinsulintherapyandmetabolic stabilizationinchildrenwithtype1diabetesmellitus.ActaDiabetol.52 (October(5)),1003–1006.
Trauzold,A.,Wermann,H.,Arlt,A.,Schutze,S.,Schafer,H.,Oestern,S.,Roder,C., Ungefroren,H.,Lampe,E.,Heinrich,M.,Walczak,H.,Kalthoff,H.,2001.CD95 andTRAILreceptor-mediatedactivationofproteinkinaseCandNF-kappaB contributestoapoptosisresistanceinductalpancreaticadenocarcinomacells. Oncogene20,4258–4269.
Trauzold,A.,Siegmund,D.,Schniewind,B.,Sipos,B.,Egberts,J.,Zorenkov,D., Emme,D.,Roder,C.,Kalthoff,H.,Wajant,H.,2006.TRAILpromotesmetastasis ofhumanpancreaticductaladenocarcinoma.Oncogene25,7434–7439. Trivedi,R.,Mishra,D.P.,2015.TrailingTRAILresistance:noveltargetsforTRAIL
sensitizationincancercells.Front.Oncol.5,69.
Tse,A.K.,Cao,H.H.,Cheng,C.Y.,Kwan,H.Y.,Yu,H.,Fong,W.F.,Yu,Z.L.,2014. IndomethacinsensitizesTRAIL-resistantmelanomacellstoTRAIL-induced apoptosisthroughROS-mediatedupregulationofdeathreceptor5and downregulationofsurvivin.J.Invest.Dermatol.134,1397–1407. Ursini-Siegel,J.,Zhang,W.,Altmeyer,A.,Hatada,E.N.,Do,R.K.,Yagita,H.,
Chen-Kiang,S.,2002.TRAIL/Apo-2ligandinducesprimaryplasmacell apoptosis.J.Immunol.169,5505–5513.
Vaccarezza,M.,Delbello,G.,Zauli,G.,2007.AroleoftheTRAIL-TRAILreceptor systeminthepathogenesisofdiabetes.ActaBioMed.78(Suppl.1),262–267. Vanhoutte,P.M.,Shimokawa,H.,Tang,E.H.,Feletou,M.,2009.Endothelial
dysfunctionandvasculardisease.ActaPhysiol.196,193–222.
Vasa,M.,Breitschopf,K.,Zeiher,A.M.,Dimmeler,S.,2000.Nitricoxideactivates telomeraseanddelaysendothelialcellsenescence.Circ.Res.87,540–542. Virag,L.,Szabo,E.,Gergely,P.,Szabo,C.,2003.Peroxynitrite-inducedcytotoxicity:
mechanismandopportunitiesforintervention.Toxicol.Lett.140–141, 113–124.
Volpato,S.,Ferrucci,L.,Secchiero,P.,Corallini,F.,Zuliani,G.,Fellin,R.,Guralnik, J.M.,Bandinelli,S.,Zauli,G.,2011.Associationoftumornecrosisfactor-related apoptosis-inducingligandwithtotalandcardiovascularmortalityinolder adults.Atherosclerosis215,452–458.
Walczak,H.,Miller,R.E.,Ariail,K.,Gliniak,B.,Griffith,T.S.,Kubin,M.,Chin,W., Jones,J.,Woodward,A.,Le,T.,Smith,C.,Smolak,P.,Goodwin,R.G.,Rauch,C.T., Schuh,J.C.,Lynch,D.H.,1999.Tumoricidalactivityoftumornecrosis factor-relatedapoptosis-inducingligandinvivo.Nat.Med.5,157–163. Wang,H.,Xu,C.,Kong,X.,Li,X.,Kong,X.,Wang,Y.,Ding,X.,Yang,Q.,2014.Trail
resistanceinducesepithelial-mesenchymaltransitionandenhances invasivenessbysuppressingPTENviamiR-221inbreastcancer.PLoSOne9, e99067.
Weidinger,A.,Kozlov,A.V.,2015.Biologicalactivitiesofreactiveoxygenand nitrogenspecies:oxidativestressversussignaltransduction.Biomolecules5, 472–484.
Weiland,U.,Haendeler,J.,Ihling,C.,Albus,U.,Scholz,W.,Ruetten,H.,Zeiher,A.M., Dimmeler,S.,2000.Inhibitionofendogenousnitricoxidesynthasepotentiates ischemia-reperfusion-inducedmyocardialapoptosisviaacaspase-3 dependentpathway.Cardiovasc.Res.45,671–678.
Wiley,S.R.,Schooley,K.,Smolak,P.J.,Din,W.S.,Huang,C.P.,Nicholl,J.K., Sutherland,G.R.,Smith,T.D.,Rauch,C.,Smith,C.A.,etal.,1995.Identification andcharacterizationofanewmemberoftheTNFfamilythatinduces apoptosis.Immunity3,673–682.
Xiang,G.,Zhang,J.,Ling,Y.,Zhao,L.,2014.CirculatinglevelofTRAILconcentration ispositivelyassociatedwithendothelialfunctionandincreasedbydiabetic therapyinthenewlydiagnosedtype2diabeticpatients.Clin.Endocrinol.80, 228–234.
Yamaguchi,H.,Wang,H.G.,2004.CHOPisinvolvedinendoplasmicreticulum stress-inducedapoptosisbyenhancingDR5expressioninhumancarcinoma cells.J.Biol.Chem.279,45495–45502.
Yerbes,R.,Palacios,C.,Lopez-Rivas,A.,2011.ThetherapeuticpotentialofTRAIL receptorsignallingincancercells.Clin.Transl.Oncol.13,839–847. Yin,W.,Li,X.,Feng,S.,Cheng,W.,Tang,B.,Shi,Y.L.,Hua,Z.C.,2009.Plasma
membranedepolarizationandNa,K-ATPaseimpairmentinducedby mitochondrialtoxinsaugmentleukemiacellapoptosisviaanovel mitochondrialamplificationmechanism.Biochem.Pharmacol.78,191–202. Yu,Y.,Lyons,T.J.,2005.Alethaltetradindiabetes:hyperglycemia,dyslipidemia, oxidativestress,andendothelialdysfunction.Am.J.Med.Sci.330,227–232.
