Interaction between docetaxel resistance and castration resistance in prostate cancer: implications of Twist1, YB-1, and androgen receptor.

BACKGROUND: Taxanes, including docetaxel, are currently the only cytotoxic chemotherapeutic agents proven to confer survival benefit in patients with castration-resistant prostate cancer (CRPC). However, the merits of taxanes remain modest, and efforts are needed to improve their therapeutic efficacy.
METHODS: We evaluated the sensitivity of prostate cancer cells to various agents using cytotoxicity assays. Gene and protein expression levels were evaluated by quantitative real-time polymerase chain reaction and Western blotting analysis, respectively.
RESULTS: Hydrogen peroxide-resistant and castration-resistant cells that overexpressed Twist1 and Y-box binding protein-1 (YB-1) were cross-resistant to cytotoxic agents, including docetaxel. Twist1 regulated YB-1 expression in prostate cancer cells, supported by the induction of Twist1 and YB-1 by transforming-growth factor-β, which is critical for taxane resistance. Twist1 and/or YB-1 were activated in docetaxel-resistant prostate cancer cells, and YB-1 was activated by docetaxel treatment. Conversely, Twist1 and YB-1 knockdown sensitized prostate cancer cells to cytotoxic agents, including docetaxel. In addition, androgen receptor (AR) knockdown increased cellular sensitivity to docetaxel, though AR expression in docetaxel-resistant LNCaP cells was paradoxically lower than in parental cells. Intriguingly, androgen deprivation treatment was more effective in docetaxel-resistant LNCaP cells compared with parental cells.
CONCLUSIONS: Twist1/YB-1 and AR signaling promote docetaxel resistance in CRPC cells. However, docetaxel-resistant cells were collaterally sensitive to androgen deprivation because of down-regulation of AR expression, suggesting that the therapeutic effect of initial taxane treatment in hormone-naïve prostate cancer may be superior to that of salvage taxane treatment in CRPC.