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.
| Original language | English |
|---|---|
| Pages (from-to) | 2376-2381 |
| Number of pages | 6 |
| Journal | Journal of Urology |
| Volume | 185 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 2011 Jun |
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Keywords
- androgen antagonists
- docetaxel
- drug resistance
- neoplasm
- prostate
- prostatic neoplasms
ASJC Scopus subject areas
- Urology
Cite this
Long-term androgen ablation and docetaxel up-regulate phosphorylated Akt in castration resistant prostate cancer. / Kosaka, Takeo; Miyajima, Akira; Shirotake, Suguru; Suzuki, Eriko; Kikuchi, Eiji; Oya, Mototsugu.
In: Journal of Urology, Vol. 185, No. 6, 06.2011, p. 2376-2381.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Long-term androgen ablation and docetaxel up-regulate phosphorylated Akt in castration resistant prostate cancer
AU - Kosaka, Takeo
AU - Miyajima, Akira
AU - Shirotake, Suguru
AU - Suzuki, Eriko
AU - Kikuchi, Eiji
AU - Oya, Mototsugu
PY - 2011/6
Y1 - 2011/6
N2 - 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.
AB - 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.
KW - androgen antagonists
KW - docetaxel
KW - drug resistance
KW - neoplasm
KW - prostate
KW - prostatic neoplasms
UR - http://www.scopus.com/inward/record.url?scp=79955847465&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79955847465&partnerID=8YFLogxK
U2 - 10.1016/j.juro.2011.02.016
DO - 10.1016/j.juro.2011.02.016
M3 - Article
C2 - 21511293
AN - SCOPUS:79955847465
VL - 185
SP - 2376
EP - 2381
JO - Journal of Urology
JF - Journal of Urology
SN - 0022-5347
IS - 6
ER -