title: Targeting ribosomal S6 kinases/Y-box binding protein-1 signaling improves cellular sensitivity to taxane in prostate cancer.
abstract: 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.
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: Momoe
authors.initials: M
authors.lastname: Itsumi
authors.forename: Akira
authors.initials: A
authors.lastname: Yokomizo
authors.forename: Ario
authors.initials: A
authors.lastname: Takeuchi
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: D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D001952:Bridged-Ring Compounds / Q000008:administration & dosage; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D017239:Paclitaxel / Q000008:administration & dosage*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D043823:Taxoids / Q000008:administration & dosage; D051840:Y-Box-Binding Protein 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001952:Bridged-Ring Compounds; D043823:Taxoids; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; C080625:taxane; D019893:Ribosomal Protein S6 Kinases; D017239:Paclitaxel
keywords: RSK; YB-1; prostate cancer; taxane