Ion channel TRPV1-dependent activation of PTP1B suppresses EGFR-associated intestinal tumorigenesis
Open Access
- 1 August 2014
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 124 (9), 3793-3806
- https://doi.org/10.1172/jci72340
Abstract
The intestinal epithelium has a high rate of turnover, and dysregulation of pathways that regulate regeneration can lead to tumor development; however, the negative regulators of oncogenic events in the intestinal epithelium are not fully understood. Here we identified a feedback loop between the epidermal growth factor receptor (EGFR), a known mediator of proliferation, and the transient receptor potential cation channel, subfamily V, member 1 (TRPV1), in intestinal epithelial cells (IECs). We found that TRPV1 was expressed by IECs and was intrinsically activated upon EGFR stimulation. Subsequently, TRPV1 activation inhibited EGFR-induced epithelial cell proliferation via activation of Ca2+/calpain and resulting activation of protein tyrosine phosphatase 1B (PTP1B). In a murine model of multiple intestinal neoplasia (ApcMin/+ mice), TRPV1 deficiency increased adenoma formation, and treatment of these animals with an EGFR kinase inhibitor reversed protumorigenic phenotypes, supporting a functional association between TRPV1 and EGFR signaling in IECs. Administration of a TRPV1 agonist suppressed intestinal tumorigenesis in ApcMin/+ mice, similar to — as well as in conjunction with — a cyclooxygenase-2 (COX-2) inhibitor, which suggests that targeting both TRPV1 and COX-2 has potential as a therapeutic approach for tumor prevention. Our findings implicate TRPV1 as a regulator of growth factor signaling in the intestinal epithelium through activation of PTP1B and subsequent suppression of intestinal tumorigenesis.Keywords
This publication has 78 references indexed in Scilit:
- Comprehensive molecular characterization of human colon and rectal cancerNature, 2012
- Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signallingNature, 2012
- The Pan-ErbB Negative Regulator Lrig1 Is an Intestinal Stem Cell Marker that Functions as a Tumor SuppressorCell, 2012
- Hedgehog signaling controls homeostasis of adult intestinal smooth muscleDevelopmental Biology, 2011
- Transient receptor potential (TRP) channels as drug targets for diseases of the digestive systemPharmacology & Therapeutics, 2011
- Paneth cells constitute the niche for Lgr5 stem cells in intestinal cryptsNature, 2010
- PTP1B: a double agent in metabolism and oncogenesisTrends in Biochemical Sciences, 2010
- TRP Channel Regulates EGFR Signaling in Hair Morphogenesis and Skin Barrier FormationCell, 2010
- ERBBs in the gastrointestinal tract: Recent progress and new perspectivesExperimental Cell Research, 2008
- Identification of stem cells in small intestine and colon by marker gene Lgr5Nature, 2007