title: Nuclear factor-kappa B and interleukin-6 related docetaxel resistance in castration-resistant prostate cancer.
abstract: BACKGROUND
  Previous work showed that the NF-κB survival pathway is activated by docetaxel (D) and contributes to D resistance in prostate cancer. In this study we aimed to investigate the dynamics of the relationship between NF-κB and IL-6 in the shift from D-naive castration-resistant prostate cancer (CRPC) to D-resistance in patients and cell lines.
  
  
  METHODS
  CRPC tumor samples were tested for NF-κB/p65 and IL-6 by immunohistochemistry. CRPC patients treated with D were also tested for serum IL-6 (ELISA). Two D-resistant cell lines, PC-3R and DU-145R, derived from the CRPC cells PC-3 and DU-145, respectively, were tested for NF-κB activation (EMSA), NF-κB-related genes expression (RT-PCR), NF-κB inhibition (p65 siRNA) and IL-6 and IL-8 soluble levels (ELISA).
  
  
  RESULTS
  In CRPC patients treated with D (n = 72), pre-treatment IL-6 level correlated with nuclear NF-κB/p65 tumor staining and response to D, and was an independent prognostic factor for overall survival. However, IL-6 level changes under treatment did not correlate with clinical outcome. In PC-3 and DU-145 parental CRPC cells, as well as in D-resistant counterparts, D treatment induced NF-κB activation. In fact, NF-κB inhibition was sufficient to re-sensitize DU-145R cells to D. Despite enhanced NF-κB activity, IL-6 secretion in D-resistant cell lines was reduced and not induced by D treatment. The same occurred with IL-8 cytokine.
  
  
  CONCLUSIONS
  These preclinical and clinical results support a role of NF-κB and IL-6 in the resistance to D in CRPC, and support the investigation of targeted therapies to enhance the antitumor activity of D in this patient population.
authors.affiliation: Medical Oncology Department and Laboratory of Translational Oncology, Hospital Clínic-Fundació Clínic per a la recerca Biomèdica, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Codony-Servat
authors.forename: Mercedes
authors.initials: M
authors.lastname: Marín-Aguilera
authors.forename: Laura
authors.initials: L
authors.lastname: Visa
authors.forename: Xabier
authors.initials: X
authors.lastname: García-Albéniz
authors.forename: Estela
authors.initials: E
authors.lastname: Pineda
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Fernández
authors.forename: Xavier
authors.initials: X
authors.lastname: Filella
authors.forename: Pere
authors.initials: P
authors.lastname: Gascón
authors.forename: Begoña
authors.initials: B
authors.lastname: Mellado
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000601:surgery; D000368:Aged; D000369:Aged, 80 and over; D000728:Androgens / Q000172:deficiency; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics*; D016209:Interleukin-8 / Q000097:blood / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000601:surgery; D034741:RNA, Small Interfering / Q000235:genetics; D043823:Taxoids / Q000627:therapeutic use*; D051996:Transcription Factor RelA / Q000235:genetics* / Q000378:metabolism
chemical_list: D000728:Androgens; D000970:Antineoplastic Agents; C508606:CXCL8 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D034741:RNA, Small Interfering; D043823:Taxoids; D051996:Transcription Factor RelA; D000077143:Docetaxel