The angiotensin II type 1 receptor antagonist telmisartan inhibits cell proliferation and tumor growth of esophageal adenocarcinoma via the AMPKα/mTOR pathway in vitro and in vivo.

Shintaro Fujihara,Hirohito Mori,Hisakazu Iwama,Tomoko Tadokoro,Kiyohito Kato,Asahiro Morishita,Hideki Kobara,Tsutomu Masaki,Taiga Chiyo,Kana Ogawa

doi:10.18632/oncotarget.14345

Shintaro Fujihara, Hirohito Mori + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.14345

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Journal: Oncotarget	Publication Date: Dec 28, 2016
Citations: 32	License type: cc-by

Affiliation: Kagawa University

Abstract

Telmisartan, a widely used antihypertensive drug, is an angiotensin II type 1 (AT1) receptor blocker (ARB). This drug inhibits cancer cell proliferation, but the underlying mechanisms in various cancers, including esophageal cancer, remain unknown. The aim of the present study was to evaluate the effects of telmisartan on human esophageal cancer cell proliferation in vitro and in vivo. We assessed the effects of telmisartan on human esophageal adenocarcinoma (EAC) cells using the cell lines OE19, OE33, and SKGT-4. Telmisartan inhibited the proliferation of these three cell lines via blockade of the G0 to G1 cell cycle transition. This blockade was accompanied by a strong decrease in cyclin D1, cyclin E, and other cell cycle-related proteins. Notably, the AMP-activated protein kinase (AMPK) pathway, a fuel sensor signaling pathway, was enhanced by telmisartan. Compound C, which inhibits the two catalytic subunits of AMPK, enhanced the expression of cyclin E, leading to G0/G1 arrest in human EAC cells. In addition, telmisartan reduced the phosphorylation of epidermal growth factor receptor (p-EGFR) and ERBB2 in vitro. In our in vivo study, intraperitoneal injection of telmisartan led to a 73.2% reduction in tumor growth in mice bearing xenografts derived from OE19 cells. Furthermore, miRNA expression was significantly altered by telmisartan in vitro and in vivo. In conclusion, telmisartan suppressed human EAC cell proliferation and tumor growth by inducing cell cycle arrest via the AMPK/mTOR pathway.

Highlights

Esophageal carcinoma is the eighth most common cancer worldwide and the sixth leading cause of cancerrelated deaths [1]
In our in vivo study, intraperitoneal injection of telmisartan led to a 73.2% reduction in tumor growth in mice bearing xenografts derived from OE19 cells
None of the other angiotensin II type receptor blockers (ARBs) affected the viability of the esophageal adenocarcinoma (EAC) cell lines (Figure 1B–1D). These results demonstrated that telmisartan strongly inhibits cell proliferation in the three EAC cell lines in a dose-dependent manner

Summary

Introduction

Esophageal carcinoma is the eighth most common cancer worldwide and the sixth leading cause of cancerrelated deaths [1]. It has one of the worst prognoses of any cancer, with a 5-year overall survival rate of approximately 15–25%. Esophageal adenocarcinoma (EAC) is less common than squamous cell carcinoma, but the frequency of adenocarcinoma of the esophagus, esophageal junction and gastric cardia has dramatically increased in Western countries [4]. Several studies have indicated that angiotensin II promotes cell proliferation during cancer development, and ARBs suppress this effect by antagonizing the AT1 receptor [6,7,8].

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