title: Preferential chemosensitization of PTEN-mutated prostate cells by silencing the Akt kinase.
abstract: 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.
authors: Department of Pharmacology, University of Milan, Milan, Italy.
authors: Marcella
authors: M
authors: Priulla
authors: Angela
authors: A
authors: Calastretti
authors: Paola
authors: P
authors: Bruno
authors: Amalia
authors: A
authors: Azzariti
authors: Azzariti
authors: A
authors: Amalia
authors: Angelo
authors: A
authors: Paradiso
authors: Gianfranco
authors: G
authors: Canti
authors: Angelo
authors: A
authors: Nicolin
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D015870:Gene Expression / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D011467:Prostate / Q000166:cytology / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D034741:RNA, Small Interfering; D050257:Tubulin Modulators; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D017239:Paclitaxel