Abstract 309: Loss of IL-6 or Stat3 drives advanced prostate cancer by promoting p53 inactivation.

Abstract

Abstract Prostate cancer is the second most common cause of death in men. Approximately 258000 men in worldwide die each year from prostate cancer. The Jak/Stat pathway (Jak - Janus kinase, Stat - signal transducer and activators of transcription) is an important signaling cascade in prostate cancer. Stat3 seems to play a fundamental role in the regulation of proliferation, apoptosis, angiogenesis and hormone-resistance in prostate cancer. Although there has been evidence for an oncogenic function of Stat3, observations from several laboratories suggest the opposite. Under certain conditions activation of Stat3 leads to decreased growth of prostate cancer cells in vitro (LNCaP) and can exert an inhibitory effect on prostate cancer xenografts. To elucidate the role of IL-6/Stat3 signaling in prostate cancer (PCa), we have established Pten-deficient (Ptenpc-/−) PCa mouse models with additional deletion of IL-6 or Stat3. Ablation of IL-6 in Ptenpc-/− mice led to increased tumor formation and signs of massive chronic inflammation. In addition, Ptenpc-/- IL-6−/- mice showed decreased expression of p53-dependent cellular senescence markers when compared to PCa in Ptenpc-/- mice. The concomitant Pten and Stat3 inactivation (Pten/Stat3pc-/−) enhanced cell proliferation and accelerated the prostate cancer progression as well as production of inflammatory cytokines. Pten/Stat3pc-/− mice showed also significant downregulation of crucial components of the p53-dependent cellular senescence pathway. Furthermore, Pten/Stat3pc-/- PCa mice revealed high expression of AR and P-Akt correlated with advanced prostate cancer. These data suggest that disruption of IL-6/Stat3 signaling promotes tumorigenesis in Ptenpc-/- induced prostate cancer via p53 inactivation. Citation Format: Jan Pencik. Loss of IL-6 or Stat3 drives advanced prostate cancer by promoting p53 inactivation. [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 309. doi:10.1158/1538-7445.AM2013-309