Abstract LB-33: TRPV1 suppresses intestinal tumorigenesis by negatively regulating EGFR signaling.

Abstract

Abstract The intestinal epithelium is the most rapidly self-renewing tissue. This dynamic process is mainly driven by Wnt, Notch and EGFR signaling in the crypts of Lieberkühn. These signaling pathways are negatively regulated by multiple control mechanisms to restrain intestinal epithelial cell (IEC) turnover and thereby reduce the risk of oncogenic transformation. Here we report a novel homeostatic feedback loop, intrinsic to IEC, between the EGFR and a member of the transient receptor potential (TRP) ion channel family. We identified that TRP vanilloid 1 (TRPV1), a polymodal pain receptor, is expressed by IEC and that this channel negatively regulates EGFR-induced cell proliferation in vivo. Intestinal crypt cultures (organoids) from Trpv1-/- mice showed hyperproliferation, crypt elongation and a reduced requirement for exogenous EGF compared to WT controls. Importantly, genetic deletion of Trpv1 increased the intestinal tumor load in multiple intestinal neoplasia (Apc+/min) mice, which was reversed by EGFR kinase inhibitor treatment. Continuous oral administration of a dietary TRPV1 agonist, capsaicin, suppressed intestinal tumorigenesis in Apc+/min mice in a TRPV1-dependent manner. In addition we found that capsaicin worked synergistically with a COX2 inhibitor, celecoxib, in the prevention of intestinal neoplasia development in these mice. Mechanistically, we show that TRPV1 is activated by EGFR signaling through phospholipase C (PLC). TRPV1 signaling subsequently restrains EGFR signaling through Ca2+-dependent triggering of protein tyrosine phosphatase (PTP) activity. Together, these findings suggest an intrinsic mechanism that exerts negative feedback on EGFR signaling through Ca2+ channel TRPV1 that thereby acts as a tumor suppressor in the intestinal epithelium. Citation Format: Petrus R. de Jong, Naoki Takahashi, Alexandra R. Harris, Jihyung Lee, Samuel Bertin, Eyal Raz. TRPV1 suppresses intestinal tumorigenesis by negatively regulating EGFR signaling. [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 LB-33. doi:10.1158/1538-7445.AM2013-LB-33