Preferential chemosensitization of PTEN-mutated prostate cells by silencing the Akt kinase

Prostate. 2007 May 15;67(7):782-9. doi: 10.1002/pros.20566.


Background: In prostate cancer, mutations of the phosphatase PTEN can activate the kinase cascade PI3K/Akt/mTOR which induces drug resistance.

Methods: Chemosensitization by siRNA targeting Akt was studied in HEK293 cells forced to express CA-Akt or kinase-dead DN-Akt. To decrease drug resistance, Akt was silenced with siRNA in human prostate DU-145 cell line expressing the normal PTEN or in LNCaP and PC3 cell lines expressing mutated-PTEN. Taxol was used for the chemosensitization studies.

Results: Silencing Akt in the drug-resistant CA-Akt cells efficiently sensitized cells to antitubule agents, whereas silencing drug-responsive DN-Akt cells did not. Only minor effects were obtained in wild-type HEK293 cells. Potentiation by siRNA of taxol cytotoxicity was significantly greater in mutated-PTEN cells than in prostate cells expressing wild-type PTEN. The apoptotic program induced by taxol was preferentially potentiated by Akt siRNA in PTEN-mutated cell lines as regards the DU-145 cell line.

Conclusions: Silencing Akt in PTEN-mutated prostate cancer cells enhances the antitumor effects of taxol. No siRNA chemosensitization was obtained in prostate cells with wild type PTEN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology
  • Cell Line
  • Cell Line, Tumor
  • Gene Expression / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Silencing / drug effects
  • Humans
  • Male
  • Mutation / genetics*
  • Oncogene Protein v-akt / genetics
  • Oncogene Protein v-akt / metabolism*
  • PTEN Phosphohydrolase / genetics*
  • PTEN Phosphohydrolase / metabolism*
  • Paclitaxel / pharmacology
  • Prostate / cytology
  • Prostate / metabolism*
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • RNA, Small Interfering / pharmacology
  • Signal Transduction
  • Tubulin Modulators / pharmacology


  • Antineoplastic Agents, Phytogenic
  • RNA, Small Interfering
  • Tubulin Modulators
  • Oncogene Protein v-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Paclitaxel