No potential conflicts of interest are reported.
Nuclear factor-kappa B and interleukin-6 related docetaxel resistance in castration-resistant prostate cancer†
Version of Record online: 4 OCT 2012
Copyright © 2012 Wiley Periodicals, Inc.
Volume 73, Issue 5, pages 512–521, April 2013
How to Cite
Codony-Servat, J., Marín-Aguilera, M., Visa, L., García-Albéniz, X., Pineda, E., Fernández, P. L., Filella, X., Gascón, P. and Mellado, B. (2013), Nuclear factor-kappa B and interleukin-6 related docetaxel resistance in castration-resistant prostate cancer. Prostate, 73: 512–521. doi: 10.1002/pros.22591
- Issue online: 14 MAR 2013
- Version of Record online: 4 OCT 2012
- Manuscript Accepted: 30 AUG 2012
- Manuscript Received: 4 JUN 2012
- castration-resistant prostate cancer;
- docetaxel resistance;
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.
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).
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.
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. Prostate 73: 512–521, 2013. © 2012 Wiley Periodicals, Inc.