Inhibition of tumor growth and sensitization to chemotherapy by RNA interference targeting interleukin-6 in the androgen-independent human prostate cancer PC3 model

The objective of the present study was to investigate the inhibitory effects of interleukin-6 (IL-6) secretion by androgen-independent human prostate cancer PC3 cells on their growth and chemosensitivity. In this study, we established PC3 in which the expression vector containing short hairpin RNA (shRNA) targeting IL-6 was introduced (PC3/sh-IL6). Changes in the growth and sensitivity to docetaxel in PC3/sh-IL6 were compared with those in PC3 transfected with control vector alone (PC3/Co). Concentration of IL-6 in the culture supernatant from PC3/sh-IL6 was approximately 20% of that from PC3/Co. Both in vitro and in vivo, the growth of PC3/sh-IL-6 was significantly inferior to that of PC3/Co, accompanying downregulation of Bcl-2, Bcl-xL, phosphorylated Akt, p44/42 mitogen-activated protein kinase, and signal transducers and activation of transcription 3 in PC3/sh-IL-6 compared with that in PC3/Co. Despite the higher sensitivity of PC3/sh-IL6 to docetaxel than that of PC3/Co, the secretion of IL-6 by both cell lines was increased after treatment with docetaxel due to the formation of positive autocrine loops between these cell lines and NF kappa B signaling pathways. Furthermore, combined treatment with the proteasome inhibitor bortezomib, which completely inhibited the docetaxel-induced IL-6 secretion via the inactivation of NF kappa B signaling, resulted in the marked sensitization of these cell lines to docetaxel both in vitro and in vivo. These findings suggest that suppressed IL-6 secretion using shRNA, either alone or in combination with docetaxel and bortezomib, could be a useful therapeutic strategy against androgen-independent prostate cancer. (Cancer Sci 2011; 102: 769-775)