Abstract 3138: IL-6/Stat3 signaling is an indispensable modulator of oncogene-induced cellular senescence

Abstract

Abstract IL-6/Stat3 signaling plays a role as a proto-oncogene in various tumors including prostate cancer, where IL-6 has been explored as therapeutic target. Deficiency of Pten, one of the most commonly mutated genes in cancer, directly triggers a senescence program critically depending on the p19Arf-p53 fail-safe pathway. We identified a novel and unexpected tumor suppressive role of IL-6/Stat3 signaling in a Pten-deficient murine prostate cancer model. Our data provide evidence that activation of IL-6/Stat3 signaling axis is implicated in oncogene-induced senescence (OIS). Strikingly, genetic ablation of IL-6 strongly promoted prostate cancer initiation, progression and metastasis in Pten-deficient mice. Mechanistically, IL6/Stat3 signaling regulates p19Arf-p53-induced senescence by modulating expression of the ubiquitin ligase MDM2 in pre-neoplastic cells. Critically, in prostate cancer patients low expression of Stat3 or p14Arf, the human homologue of p19Arf, correlates with poor survival. Therefore, the IL-6/Stat3 signaling axis may represent a novel molecular target for senescence-based cancer therapies. Citation Format: Jan Pencik, Michaela Schlederer, Melanie Hassler, Wolfgang Gruber, Fritz Aberger, Richard Kennedy, Stephen Walker, Stephan Rose-John, Valeria Poli, Robert Eferl, Harald Esterbauer, Osman Aksoy, Merima Herac, Peter Mazal, Andrea Haitel, Martin Susani, Richard Moriggl, Zoran Culig, Lukas Kenner. IL-6/Stat3 signaling is an indispensable modulator of oncogene-induced cellular senescence. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3138. doi:10.1158/1538-7445.AM2014-3138