Mitochondria and Cancer

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 . . . .