Abstract 2861: A novel negative regulation principle between DAPK and STAT3 in inflammation-associated carcinogenesis.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC It has been shown that the TNF-IL-6-STAT3 pathway plays a crucial role in promoting ulcerative colitis associated carcinoma (UCC). As inflammation compromises gut homeostasis and is associated with cancer progression, it is important to understand the role of key signalling molecules that are involved in the activation of the inflammatory cascade. Interestingly, we found that intestinal epithelial cells (IEC) of UCC in comparison to ulcerative colitis (UC) show high expression level of the anti-inflammatory Death associated protein kinase (DAPK) but only low levels of pSTAT3. Accordingly, epithelial DAPK expression was enhanced in STAT3IEC-KO mice. To unravel a possible regulatory mechanism we used an in vitro model of TNF-treated IEC. We identified a new function of DAPK in suppressing TNF-induced STAT3 activation as DAPK si knockdown and treatment with a DAPK inhibitor potentiated STAT3 activation and IL-6 secretion. DAPK attenuated STAT3 activity directly by physical interaction shown in a 3D structural model. This model suggests that DAPK induced conformational changes in the STAT3 dimer masked its nuclear localization signal. Vice versa, pharmacologic inactivation of STAT3 led to an increase in DAPK mRNA and protein levels. Chromatin immunoprecipitation data showed that STAT3 restricted DAPK expression by promoter binding, thereby reinforcing its own activation by inducing IL-6. This novel negative regulation principle was confirmed in an AOM-DSS-colon carcinogenesis mouse model. It might balance TNF-induced inflammation and seems to play an important role in the inflammation-associated transformation process. DAPK as a negative regulator of STAT3 emerges as therapeutic option in the treatment of UC and UCC. Citation Format: Saritha Chakilam, Muktheswar Gandesiri, Tilman Rau, Clemens Neufert, Abbas Agaimy, Vijayalakshmi Mahadevan, Jelena Ivanovska, Ralph Wirtz, Natalya Benderska, Jan Schulze-Luhrmann, Nadine Wittkopf, Ajithavalli Chellappan, Petra Ruemmele, Michael Vieth, Margret Rave-Frank, Hans Christiansen, Arndt Hartmann, Raja Atreya, Christoph Becker, Pablo Steinberg, Regine Schneider-Stock. A novel negative regulation principle between DAPK and STAT3 in inflammation-associated carcinogenesis. [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 2861. doi:10.1158/1538-7445.AM2013-2861 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.