title: 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.affiliation: Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Shiota
authors.forename: Akira
authors.initials: A
authors.lastname: Yokomizo
authors.forename: Ario
authors.initials: A
authors.lastname: Takeuchi
authors.forename: Momoe
authors.initials: M
authors.lastname: Itsumi
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Imada
authors.forename: Eiji
authors.initials: E
authors.lastname: Kashiwagi
authors.forename: Junichi
authors.initials: J
authors.lastname: Inokuchi
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tatsugami
authors.forename: Takeshi
authors.initials: T
authors.lastname: Uchiumi
authors.forename: Seiji
authors.initials: S
authors.lastname: Naito
mesh_terms: D001549:Benzamides; D001578:Benzopyrans / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000502:physiology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D009005:Monosaccharides / Q000494:pharmacology*; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D010766:Phosphorylation; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism; D012334:RNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051840:Y-Box-Binding Protein 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: C410798:AR protein, human; D001549:Benzamides; D001578:Benzopyrans; D009005:Monosaccharides; D009570:Nitriles; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; C497449:SL0101; D051840:Y-Box-Binding Protein 1; D010669:Phenylthiohydantoin; C540278:enzalutamide; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa
keywords: RSK; YB-1; androgen receptor; enzalutamide; prostate cancer