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Inhibition of RSK/YB-1 signaling enhances the anti-cancer effect of enzalutamide in prostate cancer.
Prostate. 2014 Jun; 74(9):959-69.P

Abstract

BACKGROUND

Previously, we have shown that Y-box binding protein-1 (YB-1) regulates androgen receptor (AR) expression and contributes to castration resistance. However, the mechanism of YB-1 activation remains unknown. In this study, we aimed to elucidate the mechanism and role of YB-1 activation in relation to castration resistance as well as enzalutamide resistance, with a view to developing a novel therapeutic concept for castration-resistant prostate cancer (CRPC) treatment.

METHODS

The expression and phosphorylation levels of ribosomal S6 kinase 1 (RSK1), YB-1 and AR were examined by quantitative PCR and Western blotting using prostate cancer cells. In addition, the effects of YB-1 inhibition using specific siRNA and small molecule inhibitor SL0101 on AR expression as well as combination treatment with enzalutamide and SL0101 were examined.

RESULTS

We found that androgen deprivation, as well as treatment with the next-generation anti-androgen enzalutamide, induced RSK1 and YB-1 activation followed by AR induction, which could be reversed by YB-1 shutdown and RSK inhibitor SL0101. SL0101 and enzalutamide exerted a synergistic tumor-suppressive effect on cell proliferation in androgen-dependent prostate cancer LNCaP cells, as well as castration-resistant C4-2 cells. Furthermore, the phosphorylation levels of RSK1 and YB-1 were elevated in castration- and enzalutamide-resistant cells, compared with their parental cells.

CONCLUSIONS

Taken together, these findings indicate that RSK1/YB-1 signaling contributes to castration as well as enzalutamide resistance, and that the therapeutic targeting of RSK1/YB-1 signaling would be a promising novel therapy against prostate cancer, especially CRPC when combined with enzalutamide.

Authors+Show Affiliations

Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24740858

Citation

Shiota, Masaki, et al. "Inhibition of RSK/YB-1 Signaling Enhances the Anti-cancer Effect of Enzalutamide in Prostate Cancer." The Prostate, vol. 74, no. 9, 2014, pp. 959-69.
Shiota M, Yokomizo A, Takeuchi A, et al. Inhibition of RSK/YB-1 signaling enhances the anti-cancer effect of enzalutamide in prostate cancer. Prostate. 2014;74(9):959-69.
Shiota, M., Yokomizo, A., Takeuchi, A., Itsumi, M., Imada, K., Kashiwagi, E., Inokuchi, J., Tatsugami, K., Uchiumi, T., & Naito, S. (2014). Inhibition of RSK/YB-1 signaling enhances the anti-cancer effect of enzalutamide in prostate cancer. The Prostate, 74(9), 959-69. https://doi.org/10.1002/pros.22813
Shiota M, et al. Inhibition of RSK/YB-1 Signaling Enhances the Anti-cancer Effect of Enzalutamide in Prostate Cancer. Prostate. 2014;74(9):959-69. PubMed PMID: 24740858.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of RSK/YB-1 signaling enhances the anti-cancer effect of enzalutamide in prostate cancer. AU - Shiota,Masaki, AU - Yokomizo,Akira, AU - Takeuchi,Ario, AU - Itsumi,Momoe, AU - Imada,Kenjiro, AU - Kashiwagi,Eiji, AU - Inokuchi,Junichi, AU - Tatsugami,Katsunori, AU - Uchiumi,Takeshi, AU - Naito,Seiji, Y1 - 2014/04/17/ PY - 2014/02/05/received PY - 2014/03/26/accepted PY - 2014/4/18/entrez PY - 2014/4/18/pubmed PY - 2014/7/2/medline KW - RSK KW - YB-1 KW - androgen receptor KW - enzalutamide KW - prostate cancer SP - 959 EP - 69 JF - The Prostate JO - Prostate VL - 74 IS - 9 N2 - BACKGROUND: Previously, we have shown that Y-box binding protein-1 (YB-1) regulates androgen receptor (AR) expression and contributes to castration resistance. However, the mechanism of YB-1 activation remains unknown. In this study, we aimed to elucidate the mechanism and role of YB-1 activation in relation to castration resistance as well as enzalutamide resistance, with a view to developing a novel therapeutic concept for castration-resistant prostate cancer (CRPC) treatment. METHODS: The expression and phosphorylation levels of ribosomal S6 kinase 1 (RSK1), YB-1 and AR were examined by quantitative PCR and Western blotting using prostate cancer cells. In addition, the effects of YB-1 inhibition using specific siRNA and small molecule inhibitor SL0101 on AR expression as well as combination treatment with enzalutamide and SL0101 were examined. RESULTS: We found that androgen deprivation, as well as treatment with the next-generation anti-androgen enzalutamide, induced RSK1 and YB-1 activation followed by AR induction, which could be reversed by YB-1 shutdown and RSK inhibitor SL0101. SL0101 and enzalutamide exerted a synergistic tumor-suppressive effect on cell proliferation in androgen-dependent prostate cancer LNCaP cells, as well as castration-resistant C4-2 cells. Furthermore, the phosphorylation levels of RSK1 and YB-1 were elevated in castration- and enzalutamide-resistant cells, compared with their parental cells. CONCLUSIONS: Taken together, these findings indicate that RSK1/YB-1 signaling contributes to castration as well as enzalutamide resistance, and that the therapeutic targeting of RSK1/YB-1 signaling would be a promising novel therapy against prostate cancer, especially CRPC when combined with enzalutamide. SN - 1097-0045 UR - https://www.unboundmedicine.com/medline/citation/24740858/Inhibition_of_RSK/YB_1_signaling_enhances_the_anti_cancer_effect_of_enzalutamide_in_prostate_cancer_ L2 - https://doi.org/10.1002/pros.22813 DB - PRIME DP - Unbound Medicine ER -