Telmisartan inhibits hepatocellular carcinoma cell proliferation in vitro by inducing cell cycle arrest

Oura,Kyoko; Tadokoro,Tomoko; Fujihara,Shintaro; Morishita,Asahiro; Chiyo,Taiga; Samukawa,Eri; Yamana,Yoshimi; Fujita,Koji; Sakamoto,Teppei; Nomura,Takako; Yoneyama,Hirohito; Kobara,Hideki; Mori,Hirohito; Iwama,Hisakazu; Okano,Keiichi; Suzuki,Yasuyuki; Masaki,Tsutomu

doi:10.3892/or.2017.5977

Telmisartan inhibits hepatocellular carcinoma cell proliferation in vitro by inducing cell cycle arrest

Authors:
- Kyoko Oura
- Tomoko Tadokoro
- Shintaro Fujihara
- Asahiro Morishita
- Taiga Chiyo
- Eri Samukawa
- Yoshimi Yamana
- Koji Fujita
- Teppei Sakamoto
- Takako Nomura
- Hirohito Yoneyama
- Hideki Kobara
- Hirohito Mori
- Hisakazu Iwama
- Keiichi Okano
- Yasuyuki Suzuki
- Tsutomu Masaki
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Affiliations: 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, Gastroenterological Surgery, Faculty of Medicine/Graduate School of Medicine, Kagawa University, Kagawa 761-0793, Japan
Published online on: September 20, 2017 https://doi.org/10.3892/or.2017.5977
Pages: 2825-2835
Copyright: © Oura et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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.

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