Inflammatory molecules facilitate the development of docetaxel-resistant prostate cancer cells in vitro and in vivo.

Numerous molecular mechanisms have been found to contribute to docetaxel-induced resistance in prostate cancer (PCa). In this study, the changes in gene expression profiles of multidrug resistant PCa cells that were established in response to docetaxel were determined using microarray analysis. In addition to alterations in the expression of multidrug resistance-associated genes, the expression levels of multiple inflammatory molecules, in particular IL-6, significantly increased in resistant cells in vitro and in vivo, which further increased with the development of drug resistance following microarray, qRT-PCR and ELISA analysis. Compared with parental cells, resistant cells also presented with stronger activation of multiple IL-6-associated signaling pathways STAT1/3, NF-κB, and PI3K/AKT. Inactivation of IL-6 using a neutralizing antibody resulted in a slight effect on the sensitivity of resistant cells to docetaxel, while blockade of of STAT1/3, NF-κB, or PI3K/AKT signaling significantly resensitized resistant cells to docetaxel. Of note, simultaneous inactivation of IL-6 and STAT1/3, PI3K/AKT or NF-κB further enhanced the sensitivity of the resistant cells to docetaxel. Thus, inflammatory molecules, in particular IL-6, and IL-6-associated signaling pathways NF-κB, STAT1/3, and PI3K/AKT, are crucial mediators of the development of docetaxel-resistance in PCa. Targeting inflammatory molecules and signaling pathways could be a potential therapeutic option for the intervention of drug resistance in PCa.