Journal Article

Ion channel TRPV1-dependent activation of PTP1B suppresses EGFR-associated intestinal tumorigenesis

Taniguchi, Koji, Bottini, Nunzio, Harris, Alexandra R., Jeffries, James, Lee, Jongdae, Niv, Yaron, Kim, Chang-Whan, de Jong, Petrus R., Stanford, Stephanie M., Bertin, Samuel, Raz, Eyal, Herdman, David S., Eckmann, Lars, Jung, Michael, Takahashi, Naoki, Lee, Jihyung, Triano, Amy I., Dong, Hui, Corr, Maripat, Duong, Jen

2014

Overview

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 (Apc(Min/+) 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 Apc(Min/+) 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.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Biomedical research / Breeding of animals / Calcium - metabolism / Calcium Channels - physiology / Calpain - physiology / Cancer / Carcinogenesis / Cell growth / Cell Proliferation / Cyclooxygenase 2 Inhibitors - pharmacology / Enzyme Activation / Homeostasis / Humans / Intestinal Neoplasms - prevention & control / Ion channels / Kinases / Mice / Oncology, Experimental / Physiological aspects / Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism / Receptor, Epidermal Growth Factor - physiology / Rodents / Signal Transduction / Studies / TRPV Cation Channels - antagonists & inhibitors / TRPV Cation Channels - physiology / Tumor suppressor genes / Tumorigenesis