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.
View: Text | PDF
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

×

Figure 7

TRPV1 signaling inhibits intestinal neoplasia development.

Options: View larger image (or click on image) Download as PowerPoint
TRPV1 signaling inhibits intestinal neoplasia development. (A) Increased...
(A) Increased tumor burden in ApcMin/+ Trpv1–/– mice. Shown are representative examples of small intestinal polyps (asterisks) in untreated and gefitinib-treated ApcMin/+ and ApcMin/+ Trpv1–/– mice. Scale bar: 4 mm. (B) 10-week-old ApcMin/+ and ApcMin/+ Trpv1–/– mice were treated with gefitinib (50 mg/kg/d) until 20 weeks, and polyps (>1 mm) were counted. n = 12 (untreated ApcMin/+), 9 (gefitinib-treated ApcMin/+ and untreated ApcMin/+ Trpv1–/–), 7 (gefitinib-treated ApcMin/+ Trpv1–/–). (C) HgB levels at 20 weeks. (D) Survival curves of ApcMin/+ and ApcMin/+ Trpv1–/– mice, treated with normal chow (n = 16 and 24, respectively) or capsaicin (Cap; n = 11 and 5, respectively). ###P = 0.0004, ApcMin/+ capsaicin vs. ApcMin/+; ***P = 0.0003, ApcMin/+ Trpv1–/– vs. ApcMin/+; P = NS, ApcMin/+ Trpv1–/– vs. ApcMin/+ Trpv1–/– capsaicin; *P = 0.019, ApcMin/+ Trpv1–/– capsaicin vs. ApcMin/+, log-rank test. (E) Increased p-EGFRY1068 and PCNA levels in ApcMin/+ Trpv1–/– colon crypts was reversed by gefitinib treatment, as in Figure 2B. (F) Increased IEC proliferation in ApcMin/+ Trpv1–/– mice. Scale bar: 100 μm. (G) Expression of EGFR- and Wnt-regulated genes in IEC lysates from 15-week-old ApcMin/+ and ApcMin/+ Trpv1–/– mice (n = 9 and 5, respectively). Mean ± SEM, expressed relative to ApcMin/+. *P < 0.05, t test. (H) ApcMin/+ mice were treated with regular chow (n = 16; different cohort from D), chow mixed with 300 ppm celecoxib (n = 9), or celecoxib plus capsaicin (n = 12). **P < 0.001, celecoxib vs. control; ***P < 0.0001, celecoxib+capsaicin vs. control; ###P = 0.0002, celecoxib+capsaicin vs. celecoxib, log-rank test. (I) Polyp counts and (J) HgB levels at 20 weeks. *P < 0.05, **P < 0.001, ***P < 0.0001 vs. control or as indicated, ANOVA (B, C, I, and J).