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.
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.
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DOI：
10.18632/oncotarget.14345
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发表时间：
2017-01-31
期刊：
影响因子：
--
通讯作者：
Masaki T
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文献类型：
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作者：
Fujihara S;Morishita A;Ogawa K;Tadokoro T;Chiyo T;Kato K;Kobara H;Mori H;Iwama H;Masaki T
替米沙坦是一种广泛使用的降压药，是一种血管紧张素Ⅱ1型(AT1)受体阻滞剂(ARB)。这种药物可以抑制癌细胞的增殖，但包括食道癌在内的各种癌症的潜在机制仍不清楚。本研究的目的是评价替米沙坦在体内外对人食道癌细胞增殖的影响。我们使用细胞系OE19、OE33和SKGT-4评估替米沙坦对人食管腺癌细胞(EAC)的影响。替米沙坦通过阻断细胞周期从G0向G1的转变来抑制这三种细胞的增殖。这种阻断伴随着细胞周期蛋白D1、细胞周期蛋白E和其他细胞周期相关蛋白的强烈减少。值得注意的是，AMP激活的蛋白激酶(AMPK)通路，一个燃料传感器信号通路，被替米沙坦增强。化合物C抑制AMPK的两个催化亚基，促进细胞周期蛋白E的表达，导致人EAC细胞G0/G1期停滞。此外，替米沙坦还在体外降低了表皮生长因子受体(p-EGFR)和ERBB2的磷酸化。在我们的活体研究中，腹腔注射替米沙坦导致携带OE19细胞来源的异种移植瘤的小鼠肿瘤生长减少73.2%。此外，替米沙坦在体外和体内均能显著改变miRNA的表达。总之，替米沙坦通过AMPK/mTOR途径诱导细胞周期停滞，从而抑制人EAC细胞的增殖和肿瘤生长。
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.