Over-expression of PTEN sensitizes human ovarian cancer cells to cisplatin-induced apoptosis in a p53-dependent manner

Gynecol Oncol. 2006 Aug;102(2):348-55. doi: 10.1016/j.ygyno.2005.12.033. Epub 2006 Mar 20.


Objective: Resistance to cisplatin-centered chemotherapy is a major cause of treatment failure in human ovarian cancer. Whereas PTEN, a tumor suppressor gene product, is believed to promote apoptosis primarily via inactivation of the PI3K/Akt cell survival pathway, recent evidence suggests that PTEN may function independently of this pathway. Activation of p53 is a key determinant of sensitivity to cisplatin-induced apoptosis. Whether PTEN can facilitate cisplatin sensitivity, and this involves the activation of p53, remains unclear. In this study, we determined whether and how PTEN over-expression sensitizes ovarian cancer cells to CDDP-induced apoptosis.

Methods and results: Using pairs of chemosensitive and chemoresistant ovarian cancer cell lines (OV20028 vs. C13* and A2780-s vs. A2780-cp) as an in vitro model, we have examined the influence of PTEN over-expression in regulation of cisplatin-induced apoptosis. Apoptosis was assessed morphologically by Hoechst staining and confirmed by the detection of cleaved products of caspase-3 and PARP by Western blot. Over-expression of PTEN by PTEN cDNA transfection up-regulates p53 content and increases the sensitivity of chemoresistant cells to cisplatin-induced apoptosis without detectable changes in the levels of phosphorylated Akt and FKHR as well as FasL mRNA abundance as determined by Western blot and RT-PCR, respectively. PTEN-mediated chemosensitization was attenuated by p53 down-regulation by siRNA in C13*, a chemoresistant wild-type p53 cell. Moreover, PTEN over-expression failed to sensitize the chemoresistant p53 mutant ovarian cancer cell line A2780-cp to cisplatin-induced apoptosis, unless wild-type p53 was reconstituted by adenoviral p53 infection.

Conclusion: Taken together, these data suggest that PTEN over-expression may represent a novel therapeutic approach for chemoresistant human ovarian cancer and that this may involve a p53-mediated apoptotic cascade independent of the PI3K/Akt pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Caspase 3
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cisplatin / pharmacology*
  • Drug Resistance, Neoplasm
  • Enzyme Activation
  • Fas Ligand Protein
  • Female
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / metabolism
  • Genetic Therapy / methods
  • Humans
  • Membrane Glycoproteins / metabolism
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology
  • PTEN Phosphohydrolase / biosynthesis*
  • PTEN Phosphohydrolase / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Transfection
  • Tumor Necrosis Factors / metabolism
  • Tumor Suppressor Protein p53 / biosynthesis
  • Tumor Suppressor Protein p53 / metabolism*


  • FASLG protein, human
  • FOXO1 protein, human
  • Fas Ligand Protein
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Membrane Glycoproteins
  • TP53 protein, human
  • Tumor Necrosis Factors
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • Cisplatin