Preferential chemosensitization of PTEN-mutated prostate cells by silencing the Akt kinase.
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.
Priulla
Marcella
M
Department of Pharmacology, University of Milan, Milan, Italy.
Calastretti
Angela
A
Bruno
Paola
P
Azzariti
Amalia
A
Amalia
Azzariti
A
Paradiso
Angelo
A
Canti
Gianfranco
G
Nicolin
Angelo
A
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
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