Nuclear factor-kappa B and interleukin-6 related docetaxel resistance in castration-resistant prostate cancer

BACKGROUND Previous work showed that the NF-B 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-B 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-B/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-B activation (EMSA), NF-B-related genes expression (RT-PCR), NF-B 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-B/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-B activation. In fact, NF-B inhibition was sufficient to re-sensitize DU-145R cells to D. Despite enhanced NF-B 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-B 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. Prostate 73: 512521, 2013. (c) 2012 Wiley Periodicals, Inc.