Ion channel TRPV1-dependent activation of PTP1B suppresses EGFR-associated intestinal tumorigenesis
Petrus R. de Jong, … , Maripat Corr, Eyal Raz
Petrus R. de Jong, … , Maripat Corr, Eyal Raz
Published August 1, 2014
Citation Information: J Clin Invest. 2014;124(9):3793-3806. https://doi.org/10.1172/JCI72340.
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Research Article Oncology

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

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.

Authors

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

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Figure 6

EGFR and TRPV1 are part of a homeostatic circuit.

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EGFR and TRPV1 are part of a homeostatic circuit. (A) EGFR triggering in...
(A) EGFR triggering induced TRPV1-mediated Ca2+ influx. CHO cells did not show Ca2+ influxes in response to EGF (100 ng/ml; green bars) when only EGFR or TRPV1 was expressed (n = 43 and 42, respectively). ATP (10 μM; red bars) served as a positive control. (B) CHO cells expressing both EGFR and TRPV1 showed [Ca2+]cyt increases in response to EGF stimulations, which was prevented by addition of exogenous PIP2 (n = 50 and 52, respectively). (C) HEK293 cells did not show EGF-induced Ca2+ responses in the presence of only EGFR or TRPV1 (n = 50 per condition). (D) HEK293 cells showed [Ca2+]cyt increases in response to EGF when EGFR and TRPV1 were coexpressed, which was prevented by PLCG1 knockdown (n = 50 and 52, respectively). HEK293 cells were transfected with control or PLCG1 siRNA, together with EGFR and TRPV1 expression plasmids. Ca2+ imaging was performed at day 3 after transfection. Mean ± SEM from individual [Ca2+]cyt measurements of Fura-2 AM–loaded cells, representative of 2 (B and D) or 3 (A and C) independent experiments.