The transcription factor, Stat3, has been implicated in the growth and progression of several cancer types including lung skin, liver, ovarian, kidney, colon cancer and prostate. Stat3 has also been shown to induce the metastatic behavior of prostate cancer cells in vitro and in vivo. Activation of Stat3 occurs by the binding of various cytokines to its receptors leading to the activation of the JAK/Stat3 signaling pathway. Of these cytokines, interleukin-6 (IL-6) has been implicated in regulating growth of various malignant tumors and activated IL-6 has been shown to be elevated in the sera from patients with metastatic prostate cancer. In the present study we examined the IL6-induced Stat3 transcriptional 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. Homozygous PTEN-mutants develop prostate cancer in a stage-specific manner and have the ability to grow and develop castration-resistant prostate cancer after total androgen ablation by castration. ELISA assays revealed increased expression of soluble IL-6 receptor (IL-6R) in tissue lysates from prostate tumors in non-castrated and castrated mice (77.0 ± 6.17 vs 23.75 ± 5.17 ng/g of tissue, p<0.001, respectively) at 32 wks of age. Immunohistochemical analysis revealed correlated expression of with Stat3 transcriptional activation, proliferation and androgen receptor in tumors from castrated mice. To determine the role of IL-6R induced transcriptional activation of Stat3, non-castrated and castrated tumor bearing mice were treated with an anti-mouse IL-6R antibody (MR-16). Mice treated with MR-16 showed downregulation of phosphorylated Stat3, however, treatment failed to inhibit tumor development and cellular proliferation. However, it was discovered that therapeutic doses of MR16 treatment resulted in increased phosphorylation of Erk1/2. Our data suggests that inhibition of IL-6R-induced Stat3 activation is insufficient to suppress tumor growth; however, further studies need to be conducted to evaluate the efficacy of horizontal combination strategies targeting Stat3 and MAP kinase signaling cascades.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3876. doi:1538-7445.AM2012-3876

©2012 American Association for Cancer Research
2012