Multiple blocks in the engagement of oxidative phosphorylation in putative ovarian cancer stem cells: implication for maintenance therapy with glycolysis inhibitors

Oncotarget. 2014 Sep 30;5(18):8703-15. doi: 10.18632/oncotarget.2367.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Biomarkers, Tumor / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Deoxyglucose / administration & dosage
  • Electron Transport Chain Complex Proteins / metabolism
  • Female
  • Glycolysis / drug effects*
  • Humans
  • Hyaluronan Receptors / metabolism
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • Maintenance Chemotherapy
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Molecular Targeted Therapy
  • Myeloid Differentiation Factor 88 / metabolism
  • Neoplasm Recurrence, Local / prevention & control
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Oxidative Phosphorylation / drug effects*
  • Paclitaxel / administration & dosage
  • Phenotype
  • RNA Interference
  • Time Factors
  • Transfection
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers, Tumor
  • CD44 protein, human
  • Electron Transport Chain Complex Proteins
  • Hyaluronan Receptors
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • Adenosine Triphosphate
  • Deoxyglucose
  • I-kappa B Kinase
  • IKBKB protein, human
  • Paclitaxel