title: Long-term androgen ablation and docetaxel up-regulate phosphorylated Akt in castration resistant prostate cancer.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Urology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Kosaka
authors.forename: Akira
authors.initials: A
authors.lastname: Miyajima
authors.forename: Suguru
authors.initials: S
authors.lastname: Shirotake
authors.forename: Eriko
authors.initials: E
authors.lastname: Suzuki
authors.forename: Eiji
authors.initials: E
authors.lastname: Kikuchi
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Oya
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use; D000818:Animals; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D043823:Taxoids / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000726:Androgen Antagonists; D043823:Taxoids; D000077143:Docetaxel; D051058:Oncogene Protein v-akt