Targeting the mitochondria activates two independent cell death pathways in ovarian cancer stem cells

Mol Cancer Ther. 2011 Aug;10(8):1385-93. doi: 10.1158/1535-7163.MCT-11-0023. Epub 2011 Jun 15.

Abstract

Cancer stem cells are responsible for tumor initiation and chemoresistance. In ovarian cancer, the CD44+/MyD88+ ovarian cancer stem cells are also able to repair the tumor and serve as tumor vascular progenitors. Targeting these cells is therefore necessary to improve treatment outcome and patient survival. The previous demonstration that the ovarian cancer stem cells are resistant to apoptotic cell death induced by conventional chemotherapy agents suggests that other forms of targeted therapy should be explored. We show in this study that targeting mitochondrial bioenergetics is a potent stimulus to induce caspase-independent cell death in a panel of ovarian cancer stem cells. Treatment of these cells with the novel isoflavone derivative, NV-128, significantly depressed mitochondrial function exhibited by decrease in ATP, Cox-I, and Cox-IV levels, and by increase in mitochondrial superoxide and hydrogen peroxide. This promotes a state of cellular starvation that activates two independent pathways: (i) AMPKα1 pathway leading to mTOR inhibition; and (ii) mitochondrial MAP/ERK kinase/extracellular signal-regulated kinase pathway leading to loss of mitochondrial membrane potential. The demonstration that a compound can specifically target the mitochondria to induce cell death in this otherwise chemoresistant cell population opens a new venue for treating ovarian cancer patients.

Publication types

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

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Adenosine Triphosphate / metabolism
  • Carcinoma, Ovarian Epithelial
  • Cell Death / drug effects
  • Electron Transport Complex I / metabolism
  • Electron Transport Complex IV / metabolism
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Humans
  • Isoflavones / pharmacology
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Neoplasms, Glandular and Epithelial / metabolism*
  • Neoplasms, Glandular and Epithelial / pathology
  • Neoplastic Stem Cells / metabolism*
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • Superoxides / metabolism
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • bcl-2-Associated X Protein / metabolism

Substances

  • Isoflavones
  • NV-128 isoflavone
  • Reactive Oxygen Species
  • bcl-2-Associated X Protein
  • Superoxides
  • Adenosine Triphosphate
  • Electron Transport Complex IV
  • TOR Serine-Threonine Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • AMP-Activated Protein Kinases
  • PRKAA1 protein, human
  • Electron Transport Complex I