title: Multiple blocks in the engagement of oxidative phosphorylation in putative ovarian cancer stem cells: implication for maintenance therapy with glycolysis inhibitors.
abstract: Survival rate in ovarian cancer has not improved since chemotherapy was introduced a few decades ago. The dismal prognosis is mostly due to disease recurrence where majority of the patients succumb to the disease. The demonstration that tumors are comprised of subfractions of cancer cells displaying heterogeneity in stemness potential, chemoresistance, and tumor repair capacity suggests that recurrence may be driven by the chemoresistant cancer stem cells. Thus to improve patient survival, novel therapies should eradicate this cancer cell population. We show that in contrast to the more differentiated ovarian cancer cells, the putative CD44+/MyD88+ ovarian cancer stem cells express lower levels of pyruvate dehydrogenase, Cox-I, Cox-II, and Cox-IV, and higher levels of UCP2. Together, this molecular phenotype establishes a bioenergetic profile that prefers the use of glycolysis over oxidative phosphorylation to generate ATP. This bioenergetic profile is conserved in vivo and therefore a maintenance regimen of 2-deoxyglucose administered after Paclitaxel treatment is able to delay the progression of recurrent tumors and decrease tumor burden in mice. Our findings strongly suggest the value of maintenance with glycolysis inhibitors with the goal of improving survival in ovarian cancer patients.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Ayesha B
authors.initials: AB
authors.lastname: Alvero
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Michele K
authors.initials: MK
authors.lastname: Montagna
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Natalia J
authors.initials: NJ
authors.lastname: Sumi
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Won Duk
authors.initials: WD
authors.lastname: Joo
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Graham
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Gil
authors.initials: G
authors.lastname: Mor
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003847:Deoxyglucose / Q000008:administration & dosage; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D005260:Female; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D060046:Maintenance Chemotherapy; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D058990:Molecular Targeted Therapy; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D017239:Paclitaxel / Q000008:administration & dosage; D010641:Phenotype; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C497483:CD44 protein, human; D045222:Electron Transport Chain Complex Proteins; D018960:Hyaluronan Receptors; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; D017239:Paclitaxel