PMID- 29048654 OWN - NLM STAT- MEDLINE DCOM- 20180723 LR - 20220410 IS - 1791-2431 (Electronic) IS - 1021-335X (Print) IS - 1021-335X (Linking) VI - 38 IP - 5 DP - 2017 Nov TI - Telmisartan inhibits hepatocellular carcinoma cell proliferation in vitro by inducing cell cycle arrest. PG - 2825-2835 LID - 10.3892/or.2017.5977 [doi] AB - 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. FAU - Oura, Kyoko AU - Oura K AD - Department of Gastroenterology and Neurology, Faculty of Medicine/Graduate School of Medicine, Kagawa University, Kagawa 761-0793, Japan. FAU - Tadokoro, Tomoko AU - Tadokoro T AD - Department of Gastroenterology and Neurology, Faculty of Medicine/Graduate School of Medicine, Kagawa University, Kagawa 761-0793, Japan. FAU - Fujihara, Shintaro AU - Fujihara S AD - Department of Gastroenterology and Neurology, Faculty of Medicine/Graduate School of Medicine, Kagawa University, Kagawa 761-0793, Japan. FAU - Morishita, Asahiro AU - Morishita A AD - Department of Gastroenterology and Neurology, Faculty of Medicine/Graduate School of Medicine, Kagawa University, Kagawa 761-0793, Japan. FAU - Chiyo, Taiga AU - Chiyo T AD - Department of Gastroenterology and Neurology, Faculty of Medicine/Graduate School of Medicine, Kagawa University, Kagawa 761-0793, Japan. FAU - Samukawa, Eri AU - Samukawa E AD - Department of Gastroenterology and Neurology, Faculty of Medicine/Graduate School of Medicine, Kagawa University, Kagawa 761-0793, Japan. FAU - Yamana, Yoshimi AU - Yamana Y AD - Department of Gastroenterology and Neurology, Faculty of Medicine/Graduate School of Medicine, Kagawa University, Kagawa 761-0793, Japan. FAU - Fujita, Koji AU - Fujita K AD - Department of Gastroenterology and Neurology, Faculty of Medicine/Graduate School of Medicine, Kagawa University, Kagawa 761-0793, Japan. FAU - Sakamoto, Teppei AU - Sakamoto T AD - Department of Gastroenterology and Neurology, Faculty of Medicine/Graduate School of Medicine, Kagawa University, Kagawa 761-0793, Japan. FAU - Nomura, Takako AU - Nomura T AD - Department of Gastroenterology and Neurology, Faculty of Medicine/Graduate School of Medicine, Kagawa University, Kagawa 761-0793, Japan. FAU - Yoneyama, Hirohito AU - Yoneyama H AD - Department of Gastroenterology and Neurology, Faculty of Medicine/Graduate School of Medicine, Kagawa University, Kagawa 761-0793, Japan. FAU - Kobara, Hideki AU - Kobara H AD - Department of Gastroenterology and Neurology, Faculty of Medicine/Graduate School of Medicine, Kagawa University, Kagawa 761-0793, Japan. FAU - Mori, Hirohito AU - Mori H AD - Department of Gastroenterology and Neurology, Faculty of Medicine/Graduate School of Medicine, Kagawa University, Kagawa 761-0793, Japan. FAU - Iwama, Hisakazu AU - Iwama H AD - Life Science Research Center, Faculty of Medicine/Graduate School of Medicine, Kagawa University, Kagawa 761-0793, Japan. FAU - Okano, Keiichi AU - Okano K AD - Gastroenterological Surgery, Faculty of Medicine/Graduate School of Medicine, Kagawa University, Kagawa 761-0793, Japan. FAU - Suzuki, Yasuyuki AU - Suzuki Y AD - Gastroenterological Surgery, Faculty of Medicine/Graduate School of Medicine, Kagawa University, Kagawa 761-0793, Japan. FAU - Masaki, Tsutomu AU - Masaki T AD - Department of Gastroenterology and Neurology, Faculty of Medicine/Graduate School of Medicine, Kagawa University, Kagawa 761-0793, Japan. LA - eng PT - Journal Article DEP - 20170920 PL - Greece TA - Oncol Rep JT - Oncology reports JID - 9422756 RN - 0 (Benzimidazoles) RN - 0 (Benzoates) RN - 0 (Cell Cycle Proteins) RN - 0 (MicroRNAs) RN - U5SYW473RQ (Telmisartan) SB - IM MH - Benzimidazoles/*pharmacology MH - Benzoates/*pharmacology MH - Carcinoma, Hepatocellular/drug therapy/*genetics MH - Cell Cycle Checkpoints MH - Cell Cycle Proteins/genetics MH - Cell Line, Tumor MH - Cell Proliferation/*drug effects MH - Gene Expression Regulation, Neoplastic/drug effects MH - Hep G2 Cells MH - Humans MH - Liver Neoplasms/drug therapy/*genetics MH - MicroRNAs/genetics MH - Telmisartan PMC - PMC5780034 EDAT- 2017/10/20 06:00 MHDA- 2018/07/24 06:00 PMCR- 2017/09/20 CRDT- 2017/10/20 06:00 PHST- 2017/03/09 00:00 [received] PHST- 2017/08/28 00:00 [accepted] PHST- 2017/10/20 06:00 [pubmed] PHST- 2018/07/24 06:00 [medline] PHST- 2017/10/20 06:00 [entrez] PHST- 2017/09/20 00:00 [pmc-release] AID - or-38-05-2825 [pii] AID - 10.3892/or.2017.5977 [doi] PST - ppublish SO - Oncol Rep. 2017 Nov;38(5):2825-2835. doi: 10.3892/or.2017.5977. Epub 2017 Sep 20.