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Preferential chemosensitization of PTEN‐mutated prostate cells by silencing the Akt kinase
Author(s) -
Priulla Marcella,
Calastretti Angela,
Bruno Paola,
Amalia Azzariti,
Paradiso Angelo,
Canti Gianfranco,
Nicolin Angelo
Publication year - 2007
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20566
Subject(s) - pten , protein kinase b , lncap , pi3k/akt/mtor pathway , cancer research , gene silencing , prostate cancer , biology , chemistry , phosphorylation , medicine , microbiology and biotechnology , signal transduction , cancer , biochemistry , gene
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. Prostate 67: 782–789, 2007. © 2007 Wiley‐Liss, Inc.