Regulation of apoptosis-inducing factor-mediated, cisplatin-induced apoptosis by Akt

Br J Cancer. 2008 Feb 26;98(4):803-8. doi: 10.1038/sj.bjc.6604223. Epub 2008 Feb 19.


Cisplatin is a first-line chemotherapeutic for ovarian cancer, although chemoresistance limits treatment success. Apoptosis, an important determinant of cisplatin sensitivity, occurs via caspase-dependent and -independent mechanisms. Activation of the protein kinase Akt, commonly observed in ovarian tumours, confers resistance to ovarian cancer cells via inhibition of caspase-dependent apoptosis. However, the effect of Akt on cisplatin-induced, caspase-independent apoptosis remains unclear. We show that in chemosensitive ovarian cancer cells, cisplatin induces the mitochondrial release and nuclear translocation of apoptosis-inducing factor (AIF), a mediator of caspase-independent apoptosis, and AIF-dependent apoptosis. Cisplatin failed to induce these effects in the chemoresistant variant cells. Overexpression of AIF sensitised resistant cells to cisplatin-induced apoptosis. Finally, activation of Akt attenuated the cisplatin-induced mitochondrial release and nuclear accumulation of AIF and apoptosis in chemosensitive cells, whereas inhibition of Akt activity facilitated these effects and sensitised chemoresistant cells to AIF-dependent, cisplatin-induced apoptosis. These results suggest that cisplatin-induced apoptosis proceeds, in part, via a caspase-independent mechanism involving AIF, and that Akt activation confers resistance to cisplatin-induced apoptosis by blocking this pathway. These results provide insights into the molecular mechanism of chemoresistance, and suggest that inhibition of Akt activity may represent a novel therapeutic approach to the treatment of cisplatin-resistant ovarian cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Apoptosis Inducing Factor / genetics
  • Apoptosis Inducing Factor / metabolism*
  • Blotting, Western
  • Caspases / metabolism
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Nucleus / pathology
  • Cisplatin / pharmacology*
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology*
  • Protein Transport
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism


  • AIFM1 protein, human
  • Apoptosis Inducing Factor
  • Proto-Oncogene Proteins c-akt
  • Caspases
  • Cisplatin