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Long-term androgen ablation and docetaxel up-regulate phosphorylated Akt in castration resistant prostate cancer

Takeo Kosaka1, Akira Miyajima, Suguru Shirotake

  • 1Department of Urology, Keio University School of Medicine, Tokyo, Japan.

The Journal of Urology
|April 23, 2011
PubMed
Abstract

Insights

Advanced prostate cancer becomes resistant to docetaxel due to increased phosphorylated Akt (a key signaling protein). This occurs during progression to castration-resistant prostate cancer under androgen deprivation therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Advanced prostate cancer often progresses to castration-resistant prostate cancer (CRPC) despite androgen ablation therapy.
  • Effective therapeutic options for advanced prostate cancer, particularly CRPC, remain limited.
  • The mechanisms driving docetaxel resistance during CRPC progression are not fully understood.

Purpose of the Study:

  • To investigate the changes in docetaxel sensitivity during the progression of prostate cancer to castration resistance under androgen ablation.
  • To examine the role of phosphorylated Akt (p-Akt) status in mediating docetaxel resistance in this context.

Main Methods:

  • Established C4-2 and C4-2AT6 cell lines, with C4-2AT6 developed under prolonged androgen ablation.
  • Assessed docetaxel sensitivity in vitro and in vivo for both cell lines.
  • Measured phosphorylated Akt levels and activity in response to docetaxel treatment.

Main Results:

  • C4-2AT6 cells exhibited significantly higher resistance to docetaxel compared to C4-2 cells.
  • This docetaxel resistance was associated with increased levels of phosphorylated Akt.
  • Docetaxel treatment dose-dependently increased phosphorylated Akt activity in C4-2AT6 cells.
  • Combined treatment with docetaxel and a PI3K/Akt inhibitor enhanced C4-2AT6 cell sensitivity to docetaxel, increasing apoptotic cell death.

Conclusions:

  • Up-regulation of phosphorylated Akt during androgen ablation contributes to docetaxel resistance in prostate cancer.
  • Further activation of phosphorylated Akt by docetaxel exacerbates this resistance.
  • These findings elucidate a mechanism underlying docetaxel resistance and progression to CRPC under androgen deprivation.

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