Redox and cancer. Part A

326 Pages·2014·10.493 MB·English

by  Danyelle M Townsend, Kenneth D Tew

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CONTRIBUTORS
NingfeiAn
DivisionofHematologyandOncology,DepartmentofMedicine,MedicalUniversityof
SouthCarolina,Charleston,SouthCarolina,USA
JosephJ.Barycki
DepartmentofBiochemistryandtheRedoxBiologyCenter,UniversityofNebraska,
Lincoln,Nebraska,USA
ArthurJ.L.Cooper
DepartmentofBiochemistryandMolecularBiology,NewYorkMedicalCollege,Valhalla,
NewYork,USA
ChristinaGrek
DepartmentofCellandMolecularPharmacologyandExperimentalTherapeutics,Medical
UniversityofSouthCarolina,Charleston,SouthCarolina,USA
MarieH.Hanigan
DepartmentofCellBiology,UniversityofOklahomaHealthSciencesCenter,Oklahoma
City,Oklahoma,USA
MerjaHeina¨niemi
DepartmentofBiotechnologyandMolecularMedicine,A.I.VirtanenInstitutefor
MolecularSciences,andInstituteofBiomedicine,SchoolofMedicine,UniversityofEastern
Finland,P.O.Box1627,Kuopio,Finland
AnnastasiaS.Hyde
DepartmentofBiochemistryandtheRedoxBiologyCenter,UniversityofNebraska,
Lincoln,Nebraska,USA
YubinKang
DivisionofHematologyandOncology,DepartmentofMedicine,MedicalUniversityof
SouthCarolina,Charleston,SouthCarolina,USA.Currentaddress:Divisionof
HematologicMalignancyandCellularTherapy/AdultBMT,DepartmentofMedicine,
DukeUniversityMedicalCenter,NorthCarolina,USA
EmiliaKansanen
DepartmentofBiotechnologyandMolecularMedicine,A.I.VirtanenInstitutefor
MolecularSciences,UniversityofEasternFinland,P.O.Box1627,Kuopio,Finland
HannaM.Leinonen
DepartmentofBiotechnologyandMolecularMedicine,A.I.VirtanenInstitutefor
MolecularSciences,UniversityofEasternFinland,P.O.Box1627,Kuopio,Finland
Anna-LiisaLevonen
DepartmentofBiotechnologyandMolecularMedicine,A.I.VirtanenInstitutefor
MolecularSciences,UniversityofEasternFinland,P.O.Box1627,Kuopio,Finland
YilinLiu
DepartmentofBiochemistryandtheRedoxBiologyCenter,UniversityofNebraska,
Lincoln,Nebraska,USA
ix
x Contributors
VolodymyrI.Lushchak
DepartmentofBiochemistryandBiotechnology,VassylStefanykPrecarpathianNational
University,Ivano-Frankivsk,Ukraine
YefimManevich
DepartmentofCellandMolecularPharmacologyandExperimentalTherapeutics,Medical
UniversityofSouthCarolina,Charleston,SouthCarolina,USA
BengtMannervik
DepartmentofChemistry-BMC,UppsalaUniversity,Uppsala,andDepartmentof
Neurochemistry,StockholmUniversity,Stockholm,Sweden
OlofMode´n
DepartmentofChemistry-BMC,UppsalaUniversity,Uppsala,Sweden
PetriPo€lo€nen
DepartmentofBiotechnologyandMolecularMedicine,A.I.VirtanenInstitutefor
MolecularSciences,andInstituteofBiomedicine,SchoolofMedicine,UniversityofEastern
Finland,P.O.Box1627,Kuopio,Finland
LijianShao
DivisionofRadiationHealth,DepartmentofPharmaceuticalSciences,WinthropP.
RockefellerCancerInstitute,UniversityofArkansasforMedicalSciences,LittleRock,
Arkansas,USA
MelanieA.Simpson
DepartmentofBiochemistryandtheRedoxBiologyCenter,UniversityofNebraska,
Lincoln,Nebraska,USA
DouglasR.Spitz
FreeRadicalandRadiationBiologyProgram,DepartmentofRadiationOncology,Holden
ComprehensiveCancerCenter,CarverCollegeofMedicine,TheUniversityofIowa,Iowa
City,Iowa,USA
KennethD.Tew
ProfessorandChairman,DepartmentofCellandMolecularPharmacology,JohnC.West
ChairofCancerResearch,MedicalUniversityofSouthCarolina,Charleston,South
Carolina,USA
DanyelleM.Townsend
DepartmentofPharmaceuticalandBiomedicalSciences,MedicalUniversityofSouth
Carolina,Charleston,SouthCarolina,USA
Zhi-WeiYe
DepartmentofCellandMolecularPharmacologyandExperimentalTherapeutics,Medical
UniversityofSouthCarolina,Charleston,SouthCarolina,USA
JieZhang
DepartmentofCellandMolecularPharmacologyandExperimentalTherapeutics,Medical
UniversityofSouthCarolina,Charleston,SouthCarolina,USA
DaohongZhou
DivisionofRadiationHealth,DepartmentofPharmaceuticalSciences,WinthropP.
RockefellerCancerInstitute,UniversityofArkansasforMedicalSciences,LittleRock,
Arkansas,USA
PREFACE
Because solid tumors frequently have reduced oxygen and altered energy
metabolism,theyalsodemonstratealteredredoxhomeostasis,bothcreating
andtoleratinghigherlevelsofreactiveoxygenandnitrogenspecies.Within
thisfirstRedoxandCancervolume,authorsvariouslydiscussthoseenzyme
systems within a cell that help regulate ROS and contribute to the unbal-
anced growth that characterizes tumor formation. The nucleophilicity of
sulfurhelpstocounteracttheROSthreat,andtumorscanhavequiteaber-
rantsmallmoleculethiolhomeostasis,thepathwaysforwhicharecomplex
and interreactive, frequently accompanied by degrees of redundancy. This
complexity provides many avenues to interrogate specific enzymes and
pathways.Forexample,glutathioneasthemostprevalentnonproteinsource
of sulfhydryls can be synthesized de novo or through salvage of constituent
amino acids. The balance of these processes depends upon numerous vari-
ables,butcanbeadistinguishingfeatureofmanytypesofcancercells.More-
over, progress in understanding recycling of GSH amino acids is facilitated
by recent progress in the crystal structure of g-glutamyl transpeptidase
(GGT), and two of the present contributions focus on the biology of this
enzyme.
The addition of glutathione to acceptor cysteines in target proteins is a
posttranslational modificationreferredto as S-glutathionylation. This alters
the size and charge of a number of proteins that can alter their structure
and/orfunction.Twochaptersdiscusstheimportanceofreversibleandirre-
versibleS-glutathionylation, processesthatyield acyclethatcontrolsmany
critical signaling events, perhaps differentially in normal and tumor cells.
Glutathione S-transferases (GST) have been the focus of oncology-based
studiesforanumberofdecades.Theirimportanceindetoxificationofsmall
molecule drugs is discussed, as is the role of a specific isozyme (GSTP) in
regulating, among other things, cellular kinase signaling and the forward
reaction of the S-glutathionylation cycle.
Thioredoxin also contributes reducing equivalents that stabilize redox
homeostasis. It can reactivate a number of enzyme systems and more
recentlyhasfoundaroleinthephysiologicalfunctioningofbonemarrow,
a tissue of high relevance in determining response to anticancer drug ther-
apies. This area of research is also covered in this volume.
xi
xii Preface
Finally,Nrf2isamastertranscriptionalregulatorandreactstochangesin
redoxenvironment.Aswillbeseen,itsregulationisfunctionallycriticalto
controlling expression of many of the gene products discussed in the other
chapters of this volume.
SubsequentvolumesofAdvancesinCancerResearchwillexpandtheredox
horizon in ways that will build upon the current contents.
CHAPTER ONE
Reactive Oxygen Species in
Normal and Tumor Stem Cells
Daohong Zhou*,1, Lijian Shao*, Douglas R. Spitz†,1
*
DivisionofRadiationHealth,DepartmentofPharmaceuticalSciences,WinthropP.RockefellerCancer
Institute,UniversityofArkansasforMedicalSciences,LittleRock,Arkansas,USA
†FreeRadicalandRadiationBiologyProgram,DepartmentofRadiationOncology,HoldenComprehensive
CancerCenter,CarverCollegeofMedicine,TheUniversityofIowa,IowaCity,Iowa,USA
1Correspondingauthors:e-mailaddress:[email protected];[email protected]
Contents
1. Introduction 2
2. ROS 3
2.1 CommonbiologicalROS 3
2.2 SourcesofROS 4
2.3 Antioxidantsandantioxidantenzymes 10
3. ROSandNormalStemCells 17
3.1 Typesofmajornormalstemcells 17
3.2 RoleofROSinstemcellphysiology 23
3.3 RoleofROSinstemcellpathology 34
4. ROSandTSCS 42
4.1 TSCs 42
4.2 ROSandLSCs 44
4.3 ROSandCSCs 46
5. Conclusion 47
Acknowledgments 47
References 48
Abstract
Reactiveoxygenspecies(ROS)playanimportantroleindeterminingthefateofnormal
stemcells.LowlevelsofROSarerequiredforstemcellstomaintainquiescenceandself-
renewal.IncreasesinROSproductioncausestemcellproliferation/differentiation,senes-
cence,andapoptosisinadose-dependentmanner,leadingtotheirexhaustion.There-
fore,theproductionofROSinstemcellsistightlyregulatedtoensurethattheyhavethe
abilitytomaintaintissuehomeostasisandrepairdamagedtissuesforthelifespanofan
organism.Inthischapter,wediscusshowtheproductionofROSinnormalstemcellsis
regulated by various intrinsic and extrinsic factors and how the fate of these cells is
alteredbythedysregulationofROSproductionundervariouspathologicalconditions.
Inaddition,theimplicationsoftheaberrantproductionofROSbytumorstemcellsfor
tumorprogressionandtreatmentarealsodiscussed.
AdvancesinCancerResearch,Volume122 #2014ElsevierInc. 1
ISSN0065-230X Allrightsreserved.
http://dx.doi.org/10.1016/B978-0-12-420117-0.00001-3
2 DaohongZhouetal.
1. INTRODUCTION
About2.5millionyearsago,cyanobacteriaevolvedtogaintheability
toproduceoxygen(O )asaby-productofphotosynthesis.O isaparamag-
2 2
neticgasthatreadilyreactswithotherelementslikehydrogen,carbon,cop-
per,andiron.AsO accumulated,itisthoughttohaveconvertedtheearly
2
reducingatmosphereintoanatmospheremoreconducivetooxidationreac-
tions. Also, as atmospheric O levels rose, many new organisms evolved
2
and flourished after developing antioxidant defense systems to protect
against the toxicity of by-products related to O metabolism. Moreover,
2
earlyaerobicorganismscontinuedevolvingtobecomemulticellularorgan-
ismsbytakingselectiveadvantageofefficientO utilizationinvariousvital
2
metabolicprocesses,suchasemployingO astheterminalelectronacceptor
2
for mitochondrial electron transport chain (ETC) activity during oxidative
phosphorylation (OXPHOS), allowing for the efficient production of
energy (Halliwell & Gutteridge, 2007).
However, utilizing O in many essential metabolic processes by living
2
systems came at an evolutionary price, because O metabolism can lead
2
to the production of reactive oxygen species (ROS) (Boveris, 1977;
Buettner, 1993; Chance, Sies, & Boveris, 1979; Forman & Kennedy,
1974, 1975; Fridovich, 1978). Fortunately, living systems are normally
maintained in a nonequilibrium steady-state that is highly reducing
and isexemplified by thereduced glutathione(GSH)/glutathione disulfide
(GSSG) redox couple that oscillates between about (cid:1)200 and (cid:1)240mV
(Schafer&Buettner,2001).Thishighlyreducingintracellularenvironment
keepssteady-stateROSatrelativelylowlevelsthatoscillatewithchangesin
metabolic activity, which can communicate normal shifts in oxidative
metabolism to signaling and gene expression pathways that control many
diversecellularfunctionsincludingcellproliferation,circadianrhythms,dif-
ferentiation,immunologicalfunctions,tissueremodeling,andvascularreac-
tivity (Beckman & Koppenol, 1996; Kessenbrock, Plaks, & Werb, 2010;
Menon & Goswami, 2007; Oberley, Oberley, & Buettner, 1980, 1981;
Reuter, Gupta, Chaturvedi, & Aggarwal, 2010; Rutter, Reick, Wu, &
McKnight,2001).IfthemetabolicproductionofROSexceedsthecapacity
of the endogenous antioxidant defense systems, oxidative stress can occur
(Sies, 1991; Spitz, Azzam, Li, & Gius, 2004). Depending on the severity
of oxidative stress, an organism may adapt by increasing its antioxidant
capacity, increasing the capacity to repair oxidative damage, or shifting
ReactiveOxygenSpeciesinNormalandTumorStemCells 3
metabolic processes away from oxidative metabolism towards glycolytic
metabolism. If the cellular adaptive processes that are induced in response
to chronic metabolic oxidative stress cannot mitigate the accumulation of
oxidative damage to critical biomolecules, potentially pathological condi-
tions can develop due to increasing oxidative damage to DNA, proteins,
andlipids.Itisthisgradualaccumulationofoxidativedamagetocriticalbio-
molecules that is believed to contribute to most if not all degenerative dis-
eases associated with aging and cancer (Droge, 2002; Finkel, 2005).
Althoughallcellsinanorganismcanbeaffectedbytheaccumulationof
oxidativedamage,theeffectsofROSonstemcells(orpluripotentcells)in
mostself-renewingtissuesareofparticularinteresttotheprocessesofaging
andcancerdevelopmentbecauseoftheirundifferentiatedstateandlongevity
ofreplicativepotential(Kobayashi&Suda,2012;Oberleyetal.,1980,1981;
Shyh-Chang,Daley,&Cantley,2013).Stemcellscanexistinacompletely
undifferentiated state, such as pluripotent embryonic stem cells (ESCs), or
canbemorecommittedtoaparticularlineageinatissueastissuestemcells
oradultstemcells(ASCs).Allnormalstemcellsappeartobehighlysensitive
to oxidative stress because of their relatively undifferentiated state with a
long division potential for accumulating genetic damage. Accumulation
of oxidative damage in normal stem cells can lead to cell transformation
and tumorigenesis or cause tissue injury, loss of function, enhanced senes-
cence, and loss of division potential associated with degenerative diseases
associated with aging (Shyh-Chang, Daley, et al., 2013). Therefore, in this
chapter,wewillfocusourdiscussionsontheroleofmetabolicROSinstem
cellphysiologyandpathologyanddiscussstrategiestoexploitthedifferences
innormalandtumorstemcell(TSC)sensitivitiestooxidativestressforselec-
tively protecting normal ASCs while sensitizing TSCs including leukemia
stemcells(LSCs)andcancerstemcells(CSCs)tooxidativedamageinduced
during leukemia and cancer therapy.
2. ROS
2.1. Common biological ROS
ROSisacollectivetermforoxygen-containingspeciesthataremorereac-
tivethanmolecularO .ThemostlikelyROStobeproducedinitiallydur-
2
ingthemetabolismofO bylivingsystemswereproposedtoderivefromthe
2
superoxide anion (O (cid:129)(cid:1)) because it represents the one-electron reduction
2
product of O (Boveris, 1977; Buettner, 1993; Chance et al., 1979;
2
Fridovich, 1978). O (cid:129)(cid:1) is a relatively weak oxidant but is an excellent
2
4 DaohongZhouetal.
reductantfortransitionmetalionssuchasFe+3,Mn+3,andCu+2leadingto
theformationofFe+2,Mn+2,andCu+1.Interestingly,approximately0.3%
ofO (cid:129)(cid:1) incellularaqueousenvironmentsisbelievedtoexistintheproton-
2
atedformasthehydroperoxylradical(HO (cid:129)).IncontrasttoO (cid:129)(cid:1),HO (cid:129)can
2 2 2
diffuse more readily through hydrophobic environments because it is
uncharged. In addition, HO (cid:129) is a much more aggressive oxidant than
2
O (cid:129)(cid:1),capableofdamagingawidevarietyofpotentiallycriticalbiomolecules
2
such as polyunsaturated fatty acidsto initiatelipid peroxidation chainreac-
tions forming ROOH and aldehydic by-products of lipid oxidation
(Buettner, 1993).
The other common ROS derived from reactions of O (cid:129)(cid:1) and HO (cid:129) in
2 2
biologicalmatricesincludehydrogenperoxide(H O ),organichydroperox-
2 2
ides(ROOH),organichydroperoxylradicals(RO (cid:129)),alkoxylradicals(RO(cid:129)),
2
andthehydroxylradical(HO(cid:129))(Buettner,1993).H O formsfromthespon-
2 2
taneousdismutationofO (cid:129)(cid:1)witharateconstantof105mol(cid:1)1s(cid:1)1orthrough
2
enzymaticdismutationofO (cid:129)(cid:1) atarateof109 mol(cid:1)1s(cid:1)1inthepresenceof
2
the superoxide dismutase (SOD) enzymes (Fridovich, 1978). ROOH are
formedfromtheoxidation of organicmolecules such as during lipid perox-
idationreactions(Buettner,1993;Buettner,Ng,Wang,Rodgers,&Schafer,
2006;Fridovich,1978).MorehighlyreactiveO radicalsarealsoformedfrom
2
Fenton-typereactionsinvolvingtransitionmetalssuchasFe+2andCu+1with
H O andROOH,respectively.Thesereactionsresultintheoxidationofthe
2 2
transition metals (to Fe+3 and Cu+2) and the formation of HO(cid:129) andorganic
hydroperoxylandalkoxylradicals(RO (cid:129)).HO(cid:129),RO (cid:129),andRO(cid:129)arepoten-
2 2
tiallyverydamagingspeciesbecausetheyareformedincloseproximitytosites
ofmetalionbindingtobiomoleculesandtheyreadilyreactwithmanycritical
biological macromolecules including lipids, proteins, and nucleic acids. For
this reason, HO(cid:129), RO(cid:129), and RO (cid:129) are thought to significantly contribute
2
to the accumulation of oxidative damage to critical biomolecules leading to
cytotoxic and mutagenic responses involved in carcinogenesis and aging
(Droge, 2002; Fridovich, 1978; Gius & Spitz, 2006; Jorgenson, Zhong, &
Oberley, 2013; Oberley et al., 1980, 1981; Spitz et al., 2004).
2.2. Sources of ROS
2.2.1 Mitochondria
Themitochondriahavebeenconsideredasamajorsourceofcellular-derived
ROSbasedonthefactthatmostcellularO consumptionoccursasaresultof
2
mitochondrialETCactivityinmammaliancells(Balaban,Nemoto,&Finkel,
2005; Boveris, 1977; Chance et al., 1979; Finkel & Holbrook, 2000;
ReactiveOxygenSpeciesinNormalandTumorStemCells 5
Forman & Kennedy, 1974, 1975; Fridovich, 1978). Mitochondrial ETCs
consist of four multiprotein complexes (complexes I–IV) assembled on the
inner mitochondrial membrane that contains a series of redox catalysts (i.e.,
pyridine nucleotides, flavoproteins, iron sulfur proteins, ubiquinone, and
cytochromes)thatutilizeelectronsobtainedfromglycolysisandthetricarbox-
ylic acid cycle to generate energy via the process of OXPHOS (Lehninger,
1976;Voet,Voet,& Pratt,1999)(Fig.1.1).TheETCproteinsarearranged
accordingtotheirredoxpotentials,andtheflowofelectronsdowntheETC
chainsisaccompaniedbythepumpingofprotonsoutoftheinnermitochon-
drial membrane creating a proton gradient ((cid:1)140 to (cid:1)180mV) across the
inner membrane that is coupled to the production of ATP from ADP+Pi
as the protons reequilibrate through the ATP synthase (also known as ETC
complex V) (Fig. 1.1). O is the terminal electron acceptor at complex IV
2
(cytochrome oxidase) where it undergoes a 4-electron reduction to form
twowatermoleculesinatightlyregulatedprocessthatisnotbelievedtoresult
intheproductionofO (cid:129)(cid:1) orH O .Despitetheefficiencyofthe4-electron
2 2 2
reductionofO toformH OatcomplexIV((cid:3)99%ofallmitochondrialO
2 2 2
consumption),thereisbelievedtobeafiniteprobabilitythat0.1–1.0%ofall
O consumedbymitochondriacanundergo1-electronreductionsatsitesin
2
complexes I, II, and III of the ETCs to form O (cid:129)(cid:1) (Ahmad et al., 2005;
2
Boveris, 1977; Boveris & Cadenas, 1982) (Fig. 1.1). Once formed, O (cid:129)(cid:1) is
2
convertedtoH O viathespontaneousorenzymaticallydrivendismutation
2 2
Figure1.1 Mitochondrialelectrontransportchainscanformsuperoxideandhydrogen
peroxidethatcanactassignalingmoleculestransducingredoxsignalsfrommetabolic
processestothenucleus.OMM,outermitochondrialmembrane;IMM,innermitochon-
drialmembrane;VDAC,voltage-dependentanionicchannel;Ref-1,redoxfactor1;FMN,
flavin mononucleotide; mPTP, mitochondrial permeability transition pore; MnSOD,
manganesesuperoxidedismutase;CuZnSOD,copper/zincsuperoxidedismutase;Cyt-
C,cytochromeC.