title: 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.
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.
authors.affiliation: Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine/Graduate School of Medicine, Kagawa 761-0793, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Fujihara
authors.affiliation: Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine/Graduate School of Medicine, Kagawa 761-0793, Japan.
authors.forename: Asahiro
authors.initials: A
authors.lastname: Morishita
authors.affiliation: Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine/Graduate School of Medicine, Kagawa 761-0793, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Ogawa
authors.affiliation: Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine/Graduate School of Medicine, Kagawa 761-0793, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tadokoro
authors.affiliation: Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine/Graduate School of Medicine, Kagawa 761-0793, Japan.
authors.forename: Taiga
authors.initials: T
authors.lastname: Chiyo
authors.affiliation: Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine/Graduate School of Medicine, Kagawa 761-0793, Japan.
authors.forename: Kiyohito
authors.initials: K
authors.lastname: Kato
authors.affiliation: Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine/Graduate School of Medicine, Kagawa 761-0793, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kobara
authors.affiliation: Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine/Graduate School of Medicine, Kagawa 761-0793, Japan.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Mori
authors.affiliation: Life Science Research Center, Kagawa University, Kagawa 761-0793, Japan.
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Iwama
authors.affiliation: Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine/Graduate School of Medicine, Kagawa 761-0793, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Masaki
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077333:Telmisartan; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D055372:AMP-Activated Protein Kinases; D047228:Angiotensin II Type 1 Receptor Blockers; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D001565:Benzoates; D018797:Cell Cycle Proteins; D066246:ErbB Receptors; D035683:MicroRNAs; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D000077333:Telmisartan; C546842:MTOR protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human
keywords: AMPKα; angiotensin II type 1 receptor blocker; cell cycle arrest; esophageal adenocarcinoma; telmisartan