title: Cyproheptadine exhibits antitumor activity in urothelial carcinoma cells by targeting GSK3β to suppress mTOR and β-catenin signaling pathways.
abstract: Cyproheptadine, a serotonin antagonist, has recently been reported to function as a novel therapeutic agent by inhibiting PI3K/AKT signaling in several human cancers. However, the therapeutic effect of cyproheptadine in urothelial carcinoma (UC) has never been explored. In this study, we determined the effect of cyproheptadine on the growth of five human UC cell lines and an in vivo xenograft model. The results showed that cyproheptadine exerted an inhibitory effect on the proliferation of UC cells both in vitro and in vivo. Cyproheptadine also induced cell cycle arrest in the G1 phase, subsequently followed by apoptosis and necrosis. The underlying mechanisms of cell cycle arrest were associated with the reduction of c-Myc, induction of p21 and p27, and the stabilization of Rb expression. In addition, the suppression of the GSK3β/TSC2/mTOR pathway and deregulation of the GSK3β/β-catenin signaling were observed in cyproheptadine-treated UC cells. Furthermore, cyproheptadine-induced apoptosis was associated with ANGPTL4 expression followed by activation of caspase3 and PARP in UC cells. Our experimental results provide evidence that cyproheptadine is a suitable therapeutic agent for the treatment of UC.
authors.affiliation: Department of Medical Research, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan; Graduate Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chiayi, Taiwan; Department of Life Science, National Chung Cheng University, 168 University Road, Min-Hsiung, Chiayi, Taiwan.
authors.forename: Hsiao-Yen
authors.initials: HY
authors.lastname: Hsieh
authors.affiliation: Department of Medical Research, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan; Department of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital, 539 Jhongsiao Road, Chiayi 600, Taiwan.
authors.forename: Cheng-Huang
authors.initials: CH
authors.lastname: Shen
authors.affiliation: Department of Radiation Oncology, Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan.
authors.forename: Ru-Inn
authors.initials: RI
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan; Department of Nursing, Chung-Jen Junior College of Nursing, Health Sciences and Management, Da-Lin, Chiayi, Taiwan.
authors.forename: Yu-Min
authors.initials: YM
authors.lastname: Feng
authors.affiliation: Graduate Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chiayi, Taiwan; Department of Life Science, National Chung Cheng University, 168 University Road, Min-Hsiung, Chiayi, Taiwan.
authors.forename: Shih-Yuan
authors.initials: SY
authors.lastname: Huang
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of General Surgery, Department of Urology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
authors.forename: Yuan-Hung
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Graduate Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chiayi, Taiwan; Department of Life Science, National Chung Cheng University, 168 University Road, Min-Hsiung, Chiayi, Taiwan.
authors.forename: Shu-Fen
authors.initials: SF
authors.lastname: Wu
authors.affiliation: Department of Medical Research, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan; Graduate Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chiayi, Taiwan; Department of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital, 539 Jhongsiao Road, Chiayi 600, Taiwan. Electronic address: cdh199712@gmail.com.
authors.forename: Cheng-Da
authors.initials: CD
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chiayi, Taiwan; Department of Life Science, National Chung Cheng University, 168 University Road, Min-Hsiung, Chiayi, Taiwan. Electronic address: biowyc@ccu.edu.tw.
authors.forename: Michael W Y
authors.initials: MW
authors.lastname: Chan
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003533:Cyproheptadine / Q000494:pharmacology*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D011985:Receptors, Serotonin / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000502:physiology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; D011985:Receptors, Serotonin; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D003533:Cyproheptadine; C546842:MTOR protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3
keywords: ANGPTL4; Cyproheptadine; Urothelial carcinoma; Wnt/β-catenin signaling; mTOR signaling