Inhibition of glucose-6-phosphate dehydrogenase sensitizes cisplatin-resistant cells to death

Oncotarget. 2015 Oct 6;6(30):30102-14. doi: 10.18632/oncotarget.4945.

Abstract

The mechanisms of cisplatin resistance, one of the major limitations of current chemotherapy, has only partially been described. We previously demonstrated that cisplatin-resistant ovarian cancer cells (C13), are characterized by reduced mitochondrial activity and higher glucose-dependency when compared to the cisplatin-sensitive counterpart (2008). In this work we further characterized the role of metabolic transformation in cisplatin resistance. By using transmitochondrial hybrids we show that metabolic reprogramming of cisplatin-resistant cell is not caused by inherent mtDNA mutations. We also found that C13 cells not only present an increased glucose-uptake and consumption, but also exhibit increased expression and enzymatic activity of the Pentose Phosphate pathway (PPP) enzyme Glucose-6-Phosphate Dehydrogenase (G6PDH). Moreover, we show that cisplatin-resistant cells are more sensitive to G6PDH inhibition. Even if the metabolomic fingerprint of ovarian cancer cells remains to be further elucidated, these findings indicate that PPP offers innovative potential targets to overcome cisplatin resistance.

Keywords: PPP; cancer metabolism; cisplatin; drug resistance; transmitochondrial hybrids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cisplatin / pharmacology*
  • DNA, Mitochondrial / genetics
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm / drug effects*
  • Energy Metabolism / drug effects*
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Glucose / metabolism
  • Glucosephosphate Dehydrogenase / antagonists & inhibitors*
  • Glucosephosphate Dehydrogenase / metabolism
  • Glutamine / metabolism
  • Humans
  • Mitochondria / drug effects*
  • Mitochondria / enzymology
  • Mitochondria / pathology
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / enzymology
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology
  • Signal Transduction / drug effects
  • Time Factors

Substances

  • Antineoplastic Agents
  • DNA, Mitochondrial
  • Enzyme Inhibitors
  • Glutamine
  • Glucosephosphate Dehydrogenase
  • Glucose
  • Cisplatin