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Interaction between docetaxel resistance and castration resistance in prostate cancer: Implications of twist1, YB‐1, and androgen receptor
Author(s) -
Shiota Masaki,
Kashiwagi Eiji,
Yokomizo Akira,
Takeuchi Ario,
Dejima Takashi,
Song YooHyun,
Tatsugami Katsunori,
Inokuchi Junichi,
Uchiumi Takeshi,
Naito Seiji
Publication year - 2013
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.22681
Subject(s) - docetaxel , taxane , prostate cancer , lncap , androgen receptor , medicine , cancer research , androgen deprivation therapy , oncology , gene knockdown , cancer cell , cancer , biology , breast cancer , apoptosis , biochemistry
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. Prostate 73:1336–1344 . © 2013 Wiley Periodicals, Inc.