Mitochondria and Cancer Hardback

Weareenteringintoaneraofre-awakeningoftheimportanceandinterestinthe role ofaltered intermediary metabolisminthedevelopmentandprogressionof malignancy.

Therefore,thisbookMitochondriaandCanceristimelyandrelevant tocontemporaryandfutureresearch,training,andeducation.

Thehallmarkstudies ofOttoWarburgetal. (1926)sparkedtheeraoftumorcellmetabolism. Fromthen untilaround1980,studiesofintermediarymetabolismofnormalandmalignant cellsweremajorareasofresearchandofgraduateandpostgraduatetrainingin biomedicalsciences.

Thisperiodwasdominatedbymitochondrialstudiesandby thoseextraordinaryoutstandingscientistswhowereaffectionatelyreferredtoasthe "mitochondriacs".

However,theadvent,development,andsubsequentdominance ofmoleculargenetics/molecularbiologyandmoleculartechnologyinbiomedical researchwereaccompaniedbythenearlycompletesubmersionofinterestinareas ofintermediarymetabolismandtumorcellmetabolism.

Forthepast30orsoyears, graduateandpostgraduatetraining,experienceandfocusinbiochemistry,meta- lism,enzymology,cellphysiologyhavedeclined,beingdisplacedbythedo- nanceofmoleculartechnologies. Therecentrevelationsandadvancesinmolecular genetics/molecularbiologyandthedevelopmentofmolecularandnanotechnology providenewdimensionstoapplytotheunderstandingandelucidationoftheroleof intermediarymetabolismandmitochondrialfunctioninthedevelopmentandp- gressionofcancers.

Toaddresstheissuesoftumormetabolism,thepresentand futuregenerationsofresearchersmustintegratetheknowledgeandmethods of biochemistrywiththeknowledgeandtechnologyofmolecularbiology.

Thefocusonmitochondriaiscentraltodiscussionsandissuesofintermediary metabolism.

Thegenetictransformationofnormalfunctionalcellstoneoplastic cellsimposestheneedforalterationsinintermediarymetabolismandmitochond- alfunctiontoprovidethebioenergetic/synthetic/growthrequirementsforthep- gression of the neoplastic cell to malignancy.

In the absence of the metabolic transformation,theneoplasticmalignantcellwillnotachieveitsmalignantpot- tial.

Thus,itiscriticaltoestablishtheroleofthemitochondriainthemalignant process.

Moreover,speci?calterationsindifferentcancertypesmustbeidenti?ed.

Such information will provide new approaches to the treatment and perhaps preventionofdifferingcancers. TheadventofMetabolomicsforthedetectionof v vi Preface cancer and progression of malignancy is dependent upon the elucidation and identi?cationofalteredmetabolismandmitochondrialfunction.

Thus,thisexciting journeyincancerresearchhasbarelybegunandhasalongwaytogo.

Thisbook, Mitochondria and Cancer, and its subject matter provide a roadmap and the preparationtoproceedonthisjourney.

Wearegreatlyindebtedtothecontributingauthorsfortheirenthusiasticsupport andwritingachapterintheirareaofexpertise.

WearegratefultoMs. DonnaOvak for secretarial help and our families for their patience and support in putting togetherthisbook.

Thisbookisdedicatedtopast,present,andfuture"mitoch- driacs"aroundtheworld.

Buffalo,NY KeshavK. Singh Baltimore,MD LeslieC. Costello Contents MitochondriaandCancer...1 KjerstinM.

Owens,J. S. Modica-Napolitano,andKeshavK. Singh WarburgandhisLegacy ...23 MichaelRistowandTimJ.

Schulz TheLipogenicSwitchinCancer...39 KoenBrusselmansandJohannesV.

Swinnen CitrateMetabolisminProstateandOtherCancers ...61 RentyB.

FranklinandLeslieC. Costello IntegrationofGenetic,Proteomic,andMetabolicApproachesin TumorCellMetabolism ...79 LeslieC.

CostelloandRentyB. Franklin MitochondrialRespirationandDifferentiation ...93 RobertoScatena,PatriziaBottoni,andBrunoGiardina IntegrationofEnergyMetabolismandControlofApoptosis inTumorCells ...103 JohnG.

PastorinoandJanB. Hoek EnergyGeneratingPathwaysandtheTumorSuppressorp53 ...131 ChadA.

Corcoran,YingHuang,andM. SaeedSheikh MitochondrialTumorSuppressors...151 BoraE.

Baysal MitochondriainHematology ...163 StefanieZanssen vii viii Contents MitochondriaandOncocytomas...193 J.

Lima,V. Ma'ximo,P. Soares,R. Portugal,S. Guimara"es, andM. Sobrinho-Simo"es MitochondriaasTargetsforCancerTherapy...211 StephenJ.

RalphandJiriNeuzil ReversingtheWarburgEffect:MetabolicModulationasa NovelCancerTherapy...251 GopinathSutendraandEvangelosD.

Michelakis MitochondrialNanotechnologyforCancerTherapy ...265 VolkmarWeissig,GerardG.

M. D'. However,theadvent,development,andsubsequentdominance ofmoleculargenetics/molecularbiologyandmoleculartechnologyinbiomedical researchwereaccompaniedbythenearlycompletesubmersionofinterestinareas ofintermediarymetabolismandtumorcellmetabolism. Forthepast30orsoyears, graduateandpostgraduatetraining,experienceandfocusinbiochemistry,meta- lism,enzymology,cellphysiologyhavedeclined,beingdisplacedbythedo- nanceofmoleculartechnologies.

Therecentrevelationsandadvancesinmolecular genetics/molecularbiologyandthedevelopmentofmolecularandnanotechnology providenewdimensionstoapplytotheunderstandingandelucidationoftheroleof intermediarymetabolismandmitochondrialfunctioninthedevelopmentandp- gressionofcancers.

Toaddresstheissuesoftumormetabolism,thepresentand futuregenerationsofresearchersmustintegratetheknowledgeandmethods of biochemistrywiththeknowledgeandtechnologyofmolecularbiology.

Thefocusonmitochondriaiscentraltodiscussionsandissuesofintermediary metabolism.

Thegenetictransformationofnormalfunctionalcellstoneoplastic cellsimposestheneedforalterationsinintermediarymetabolismandmitochond- alfunctiontoprovidethebioenergetic/synthetic/growthrequirementsforthep- gression of the neoplastic cell to malignancy.

In the absence of the metabolic transformation,theneoplasticmalignantcellwillnotachieveitsmalignantpot- tial.

Thus,itiscriticaltoestablishtheroleofthemitochondriainthemalignant process.

Moreover,speci?calterationsindifferentcancertypesmustbeidenti?ed.

Such information will provide new approaches to the treatment and perhaps preventionofdifferingcancers.

TheadventofMetabolomicsforthedetectionof v vi Preface cancer and progression of malignancy is dependent upon the elucidation and identi?cationofalteredmetabolismandmitochondrialfunction.

Thus,thisexciting journeyincancerresearchhasbarelybegunandhasalongwaytogo.

Thisbook, Mitochondria and Cancer, and its subject matter provide a roadmap and the preparationtoproceedonthisjourney.

Wearegreatlyindebtedtothecontributingauthorsfortheirenthusiasticsupport andwritingachapterintheirareaofexpertise.

WearegratefultoMs. DonnaOvak for secretarial help and our families for their patience and support in putting togetherthisbook.

Thisbookisdedicatedtopast,present,andfuture"mitoch- driacs"aroundtheworld.

Buffalo,NY KeshavK. Singh Baltimore,MD LeslieC. Costello Contents MitochondriaandCancer...1 KjerstinM.

Owens,J. S. Modica-Napolitano,andKeshavK. Singh WarburgandhisLegacy ...23 MichaelRistowandTimJ.

Schulz TheLipogenicSwitchinCancer...39 KoenBrusselmansandJohannesV.

Swinnen CitrateMetabolisminProstateandOtherCancers ...61 RentyB.

FranklinandLeslieC. Costello IntegrationofGenetic,Proteomic,andMetabolicApproachesin TumorCellMetabolism ...79 LeslieC.

CostelloandRentyB. Franklin MitochondrialRespirationandDifferentiation ...93 RobertoScatena,PatriziaBottoni,andBrunoGiardina IntegrationofEnergyMetabolismandControlofApoptosis inTumorCells ...103 JohnG.

PastorinoandJanB. Hoek EnergyGeneratingPathwaysandtheTumorSuppressorp53 ...131 ChadA.

Corcoran,YingHuang,andM. SaeedSheikh MitochondrialTumorSuppressors...151 BoraE.

Baysal MitochondriainHematology ...163 StefanieZanssen vii viii Contents MitochondriaandOncocytomas...193 J.

Lima,V. Ma'ximo,P. Soares,R. Portugal,S. Guimara"es, andM. Sobrinho-Simo"es MitochondriaasTargetsforCancerTherapy...211 StephenJ.

RalphandJiriNeuzil ReversingtheWarburgEffect:MetabolicModulationasa NovelCancerTherapy...251 GopinathSutendraandEvangelosD.

Michelakis MitochondrialNanotechnologyforCancerTherapy ...265 VolkmarWeissig,GerardG.

M. D'Souza,Shing-MingCheng, andSarathiBoddapati Index ...281 Contributors BoraE.

Baysal DepartmentofPathology,YaleUniversitySchoolofMedicine,310CedarStreet, NewHaven,CT06520-8023,USA,bora. baysal@yale. edu SarathiBoddapati Department of Pharmaceutical Sciences, Midwestern University College of PharmacyGlendale,Glendale,AZ,USA PatriziaBottoni DipartimentodiMedicinadiLaboratorio,Universita' CattolicadelSacroCuore, LargoA. Gemelli8,00168Rome,Italy KoenBrusselmans LaboratoryforExperimentalMedicineandEndocrinology,KatholiekeUniversiteit Leuven,Leuven,Belgium Shing-MingCheng Department of Pharmaceutical Sciences, Midwestern University College of PharmacyGlendale,Glendale,AZ,USA ChadA.