Interleukin-6 or IL-6 is a pleiotropic cytokine which is implicated in the regulation of immune response, but is also involved in regulating the growth of various malignant tumors. Mounting evidence suggests that IL-6 contributes to prostate cancer progression. Activated IL-6 has been shown to be elevated in the sera from patients with metastatic prostate cancer and it appears that the prostate tissue itself is a source of IL-6 and its receptor. Experimental data suggests that the IL-6/IL-6R signaling axis is an autocrine and paracrine growth factor in androgen independent prostate cancer cell lines and can activate a variety of signal transduction cascades, some of which may activate androgen receptor activity. In the present study we examined the role of IL6-induced Stat3 activation in the development and progression of prostate cancer and its possible role as a target for the treatment of prostate cancer using the prostate-specific conditional targeting PTEN knockout mouse model. In PTEN-mutant mice, elevated levels of IL6/IL-6R correlated with increased cellular proliferation in non-castrate and castrate prostate cancer (CRPC). Similar to human prostate cancer, mice with CPRC showed elevated levels of IL-6 and IL6-R in both serum and prostate tissue. To establish a therapeutic role for IL6/IL6R inhibition, we conducted a series of pharmacodynamic studies using an anti-mouse IL-6R antibody (MR-16) in tumor bearing homozygous PTEN-mutant mice. Our data shows that STAT3 activation was inhibited in a dose dependent manner during acute IL6-R blockade. Inhibition of STAT3 activity after chronic IL-6R blockade was transient. However, at day 45 of treatment, tumor cell proliferation was inhibited and apoptosis was induced. These findings show that this mouse model is relevant for the study of Stat3 signaling and tumor progression and inhibition of Stat3 transcriptional activation by upstream signal blockade may be a promising approach for molecularly targeted therapeutic strategies in human prostate cancer. Thus this study will serve as the foundation for future drug intervention studies designed to assess the efficacy of targeting the JAK/STAT signal pathway using targeted monotherapy and combination drug therapy models.

Citation Format: Yurie Kura, Marco A. De Velasco, Yasuyuki Kobayashi, Naomi Ando, Emiko Fukushima, Yutaka Yamamoto, Yuji Hatanaka, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Interleukin-6 (IL-6) as a therapeutic target in prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1226. doi:10.1158/1538-7445.AM2013-1226

©2013 American Association for Cancer Research
2013