イツミ　モモエ   逸見　百江    所属   川崎医科大学  医学部 一般教養　自然科学    職種   助教
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Targeting ribosomal S6 kinases/Y-box binding protein-1 signaling improves cellular sensitivity to taxane in prostate cancer.
掲載誌名	正式名：The Prostate 略　 称：Prostate ISSNコード：10970045/02704137
掲載区分	国外
巻・号・頁	74(8),pp.829-38
著者・共著者	Masaki Shiota, Momoe Itsumi, Akira Yokomizo, Ario Takeuchi, Kenjiro Imada, Eiji Kashiwagi, Junichi Inokuchi, Katsunori Tatsugami, Takeshi Uchiumi, Seiji Naito
発行年月	2014/06
概要	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.
DOI	10.1002/pros.22799
PMID	24729449