Department of Gastroenterology and Neurology, Faculty of Medicine/Graduate School of Medicine, Kagawa University, Kagawa 761-0793, Japan.
Life Science Research Center, Faculty of Medicine/Graduate School of Medicine, Kagawa University, Kagawa 761-0793, Japan.
Oncol Rep. 2017 Nov;38(5):2825-2835. doi: 10.3892/or.2017.5977. Epub 2017 Sep 20.
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third leading cause of cancer-related death. Telmisartan, a widely used antihypertensive drug, is an angiotensin II type 1 (AT1) receptor blocker (ARB) that might inhibit cancer cell proliferation, but the mechanisms through which telmisartan affects various cancers remain unknown. The aim of the present study was to evaluate the effects of telmisartan on human HCC and to assess the expression of microRNAs (miRNAs). We studied the effects of telmisartan on HCC cells using the HLF, HLE, HepG2, HuH-7 and PLC/PRF/5 cell lines. In our experiments, telmisartan inhibited the proliferation of HLF, HLE and HepG2 cells, which represent poorly differentiated types of HCC cells. However, HuH-7 and PLC/PRF/5 cells, which represent well-differentiated types of HCC cells, were not sensitive to telmisartan. Telmisartan induced G0/G1 cell cycle arrest of HLF cells by inhibiting the G0-to-G1 cell cycle transition. This blockade was accompanied by a marked decrease in the levels of cyclin D1, cyclin E and other cell cycle-related proteins. Notably, the activity of the AMP-activated protein kinase (AMPK) pathway was increased, and the mammalian target of rapamycin (mTOR) pathway was inhibited by telmisartan treatment. Additionally, telmisartan increased the level of caspase-cleaved cytokeratin 18 (cCK18), partially contributed to the induction of apoptosis in HLF cells and reduced the phosphorylation of ErbB3 in HLF cells. Furthermore, miRNA expression was markedly altered by telmisartan in vitro. In conclusion, telmisartan inhibits human HCC cell proliferation by inducing cell cycle arrest.
肝细胞癌（HCC）是最常见的肝脏原发性恶性肿瘤，也是癌症相关死亡的第三大主要原因。替米沙坦是一种广泛用于治疗高血压的药物，是血管紧张素 II 型 1（AT1）受体阻滞剂（ARB），可能抑制癌细胞增殖，但替米沙坦影响各种癌症的机制尚不清楚。本研究旨在评估替米沙坦对人 HCC 的影响，并评估 microRNAs（miRNAs）的表达。我们使用 HLF、HLE、HepG2、HuH-7 和 PLC/PRF/5 细胞系研究了替米沙坦对 HCC 细胞的影响。在我们的实验中，替米沙坦抑制了 HLF、HLE 和 HepG2 细胞的增殖，这些细胞代表 HCC 细胞的低分化类型。然而，HuH-7 和 PLC/PRF/5 细胞，代表 HCC 细胞的高分化类型，对替米沙坦不敏感。替米沙坦通过抑制 G0 到 G1 细胞周期转换，诱导 HLF 细胞 G0/G1 细胞周期停滞。这种阻滞伴随着细胞周期相关蛋白 cyclin D1、cyclin E 等水平的显著降低。值得注意的是，替米沙坦增加了 AMP 激活的蛋白激酶（AMPK）通路的活性，抑制了哺乳动物雷帕霉素靶蛋白（mTOR）通路。此外，替米沙坦增加了 caspase 切割细胞角蛋白 18（cCK18）的水平，部分促进了 HLF 细胞的凋亡，并减少了 HLF 细胞中 ErbB3 的磷酸化。此外，替米沙坦在体外显著改变了 miRNA 的表达。总之，替米沙坦通过诱导细胞周期停滞抑制人 HCC 细胞增殖。
