Long-Term Androgen Ablation and Docetaxel Up-Regulate Phosphorylated Akt in Castration Resistant Prostate Cancer

No AccessJournal of UrologyInvestigative Urology1 Jun 2011Long-Term Androgen Ablation and Docetaxel Up-Regulate Phosphorylated Akt in Castration Resistant Prostate Cancer Takeo Kosaka, Akira Miyajima, Suguru Shirotake, Eriko Suzuki, Eiji Kikuchi, and Mototsugu Oya Takeo KosakaTakeo Kosaka More articles by this author , Akira MiyajimaAkira Miyajima More articles by this author , Suguru ShirotakeSuguru Shirotake More articles by this author , Eriko SuzukiEriko Suzuki More articles by this author , Eiji KikuchiEiji Kikuchi More articles by this author , and Mototsugu OyaMototsugu Oya More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.016AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: There are still few effective therapeutic options for advanced prostate cancer. One of the most troublesome aspects of prostate cancer is that androgen dependent prostate cancer inevitably progresses to highly aggressive, life threatening castration resistant prostate cancer after androgen ablation therapy. To our knowledge it remains unknown how sensitivity to docetaxel changes during progression to more aggressive castration resistant prostate cancer under androgen ablation. Materials and Methods: We investigated sensitivity to docetaxel and phosphorylated Akt status in C4-2 and C4-2AT6 cells established at our institution. Results: C4-2AT6 cells established under androgen ablation conditions for 6 months showed significantly higher resistance to docetaxel than C4-2 cells in vivo and in vitro. Resistance was accompanied by increased phosphorylated Akt. In C4-2AT6 cells phosphorylated Akt activity was significantly up-regulated by docetaxel in a dose dependent manner. After treatment with docetaxel and a phosphatidylinositol 3-kinase/Akt inhibitor the sensitivity of C4-2AT6 cells to docetaxel markedly increased through enhanced apoptotic death. Conclusions: Findings indicated that up-regulation of phosphorylated Akt during androgen ablation and its further activation by docetaxel explains at least in part the resistance to docetaxel and progression to castration resistant prostate cancer under androgen ablation conditions. References 1 : Management of cancer of the prostate. N Engl J Med1994; 331: 996. Google Scholar 2 : Cancer statistics, 2009. CA Cancer J Clin2009; 59: 225. Google Scholar 3 : Current indications for chemotherapy in prostate cancer patients. Eur Urol2007; 51: 17. Google Scholar 4 : Ets-1 and hypoxia inducible factor-1alpha inhibition by angiotensin II type-1 receptor blockade in hormone-refractory prostate cancer. Prostate2010; 70: 162. 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Volume 185Issue 6June 2011Page: 2376-2381 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.Keywordsprostatic neoplasmsandrogen antagonistsdrug resistancedocetaxelprostateneoplasmMetricsAuthor Information Takeo Kosaka More articles by this author Akira Miyajima More articles by this author Suguru Shirotake More articles by this author Eriko Suzuki More articles by this author Eiji Kikuchi More articles by this author Mototsugu Oya More articles by this author Expand All Advertisement PDF downloadLoading ...