Inhibition of RSK/YB-1 signaling enhances the anti-cancer effect of enzalutamide in prostate cancer.

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: Masaki Shiota, Akira Yokomizo, Ario Takeuchi, Momoe Itsumi, Kenjiro Imada, Eiji Kashiwagi, Junichi Inokuchi, Katsunori Tatsugami, Takeshi Uchiumi, Seiji Naito
• Journal: The Prostate (Prostate) Vol. 74 Issue 9 Pg. 959-69 (Jun 2014) ISSN: 1097-0045 [Electronic] United States
• PMID: 24740858 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

• AR protein, human
• Benzamides
• Benzopyrans
• Monosaccharides
• Nitriles
• RNA, Neoplasm
• RNA, Small Interfering
• Receptors, Androgen
• SL0101
• Y-Box-Binding Protein 1
• Phenylthiohydantoin
• enzalutamide
• RPS6KA1 protein, human
• Ribosomal Protein S6 Kinases, 90-kDa

Topics

• Benzamides
• Benzopyrans (pharmacology)
• Blotting, Western
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (physiology)
• Drug Synergism
• Drug Therapy, Combination
• Humans
• Male
• Monosaccharides (pharmacology)
• Nitriles
• Phenylthiohydantoin (analogs & derivatives, pharmacology)
• Phosphorylation
• Prostatic Neoplasms, Castration-Resistant (drug therapy, metabolism)
• RNA, Neoplasm (chemistry, genetics)
• RNA, Small Interfering (pharmacology)
• Real-Time Polymerase Chain Reaction
• Receptors, Androgen (genetics, metabolism)
• Ribosomal Protein S6 Kinases, 90-kDa (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction (drug effects)
• Y-Box-Binding Protein 1 (antagonists & inhibitors, genetics, metabolism)