title: Interaction between docetaxel resistance and castration resistance in prostate cancer: implications of Twist1, YB-1, and androgen receptor.
abstract: BACKGROUND
  Taxanes, including docetaxel, are currently the only cytotoxic chemotherapeutic agents proven to confer survival benefit in patients with castration-resistant prostate cancer (CRPC). However, the merits of taxanes remain modest, and efforts are needed to improve their therapeutic efficacy.
  
  
  METHODS
  We evaluated the sensitivity of prostate cancer cells to various agents using cytotoxicity assays. Gene and protein expression levels were evaluated by quantitative real-time polymerase chain reaction and Western blotting analysis, respectively.
  
  
  RESULTS
  Hydrogen peroxide-resistant and castration-resistant cells that overexpressed Twist1 and Y-box binding protein-1 (YB-1) were cross-resistant to cytotoxic agents, including docetaxel. Twist1 regulated YB-1 expression in prostate cancer cells, supported by the induction of Twist1 and YB-1 by transforming-growth factor-β, which is critical for taxane resistance. Twist1 and/or YB-1 were activated in docetaxel-resistant prostate cancer cells, and YB-1 was activated by docetaxel treatment. Conversely, Twist1 and YB-1 knockdown sensitized prostate cancer cells to cytotoxic agents, including docetaxel. In addition, androgen receptor (AR) knockdown increased cellular sensitivity to docetaxel, though AR expression in docetaxel-resistant LNCaP cells was paradoxically lower than in parental cells. Intriguingly, androgen deprivation treatment was more effective in docetaxel-resistant LNCaP cells compared with parental cells.
  
  
  CONCLUSIONS
  Twist1/YB-1 and AR signaling promote docetaxel resistance in CRPC cells. However, docetaxel-resistant cells were collaterally sensitive to androgen deprivation because of down-regulation of AR expression, suggesting that the therapeutic effect of initial taxane treatment in hormone-naïve prostate cancer may be superior to that of salvage taxane treatment in CRPC.
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: Eiji
authors.initials: E
authors.lastname: Kashiwagi
authors.forename: Akira
authors.initials: A
authors.lastname: Yokomizo
authors.forename: Ario
authors.initials: A
authors.lastname: Takeuchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Dejima
authors.forename: Yoohyun
authors.initials: Y
authors.lastname: Song
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tatsugami
authors.forename: Junichi
authors.initials: J
authors.lastname: Inokuchi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Uchiumi
authors.forename: Seiji
authors.initials: S
authors.lastname: Naito
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use; D045744:Cell Line, Tumor; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D043823:Taxoids / Q000378:metabolism* / Q000627:therapeutic use; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*; D051840:Y-Box-Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C410798:AR protein, human; D000970:Antineoplastic Agents; D009687:Nuclear Proteins; D011944:Receptors, Androgen; C103173:TWIST1 protein, human; D043823:Taxoids; D051879:Twist-Related Protein 1; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D000077143:Docetaxel
keywords: CRPC; Twist1; YB-1; androgen receptor; docetaxel