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Targeting ribosomal S6 kinases/Y‐box binding protein‐1 signaling improves cellular sensitivity to taxane in prostate cancer
Author(s) -
Shiota Masaki,
Itsumi Momoe,
Yokomizo Akira,
Takeuchi Ario,
Imada Kenjiro,
Kashiwagi Eiji,
Inokuchi Junichi,
Tatsugami Katsunori,
Uchiumi Takeshi,
Naito Seiji
Publication year - 2014
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.22799
Subject(s) - taxane , ribosomal s6 kinase , prostate cancer , cancer research , kinase , mapk/erk pathway , paclitaxel , gene knockdown , docetaxel , cancer , signal transduction , medicine , biology , chemistry , microbiology and biotechnology , apoptosis , pi3k/akt/mtor pathway , p70 s6 kinase 1 , biochemistry , breast cancer
BACKGROUND Taxanes are the only cytotoxic chemotherapeutic agents proved to prolong the survival in patients with castration‐resistant prostate cancer. However, because of intrinsic and acquired resistances to taxanes, their therapeutical efficiencies are modest, bringing only a few months of survival benefit. Y‐box binding protein‐1 (YB‐1) promotes cancer cell resistance to various anticancer treatments, including taxanes. Here, we aimed to elucidate the mechanism of taxane resistance by YB‐1 and examined overcoming resistance by targeting YB‐1 signaling. METHODS Gene and protein expression levels were evaluated by quantitative real‐time polymerase chain reaction and Western blot analysis, respectively. We evaluated the sensitivity of prostate cancer cells to taxanes using cytotoxicity assays. RESULTS Natural taxane paclitaxel from Taxus brevifolia activated the Raf‐1/extracellular signal‐regulated kinase (ERK) pathway, leading to an activation of ribosomal S6 kinases (RSK)/YB‐1 signaling. Activated Raf‐1/ERK pathway was blunted by YB‐1 knockdown in prostate cancer cells, indicating regulation between Raf‐1/ERK signaling and YB‐1. In addition, ERK or RSK was activated in taxane‐resistant prostate cancer cells, resulting in YB‐1 activation. YB‐1 knockdown as well as RSK inhibition using RSK‐specific siRNA or the small molecule inhibitor SL0101 successfully blocked activation of YB‐1, leading to suppression of prostate cancer growth and sensitization to paclitaxel. CONCLUSIONS Taken together, these findings indicate that RSK/YB‐1 signaling contributes to taxane resistance, and implicate the therapeutics targeting RSK/YB‐1 signaling such as RSK inhibitor as a promising novel therapy against prostate cancer, especially in combination with taxane. Prostate 74:829–838, 2014 . © 2014 Wiley Periodicals, Inc.