title: TRPM7 channel inhibition mediates midazolam-induced proliferation loss in human malignant glioma.
abstract: The melastatin-like transient receptor potential 7 (TRPM7) has been implicated in proliferation or apoptosis of some cancers, indicating the potential of TRPM7 as an anti-anaplastic target. Here, we identified the characteristic TRPM7 channel currents in human malignant glioma MGR2 cells, which could be blocked by a pharmacologic inhibitor Gd3+. We mined the clinical sample data from Oncomine Database and found that human malignant glioma tissues expressed higher TRPM7 mRNA than normal brain ones. Importantly, we identified a widely used clinical anesthetic midazolam as a TRPM7 inhibitor. Midazolam treatment for seconds suppressed the TRPM7 currents and calcium influx, and treatment for 48 h inhibited the TRPM7 expression. The inhibitory effect on TRPM7 accounts for the proliferation loss and G0/G1phase cell cycle arrest induced by midazolam. Our data demonstrates that midazolam represses proliferation of human malignant glioma cells through inhibiting TRPM7 currents, which may be further potentiated by suppressing the expression of TRPM7. Our result indicates midazolam as a pharmacologic lead compound with brain-blood barrier permeability for targeting TRPM7 in the glioma.
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.|School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, People's Republic of China.
authors.forename: Jingkao
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, Department of Pathology and Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.
authors.forename: Yunling
authors.initials: Y
authors.lastname: Dou
authors.affiliation: Department of Anesthesiology, Department of Pathology and Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, 30329, USA.
authors.forename: Tiandong
authors.initials: T
authors.lastname: Leng
authors.affiliation: Department of Anesthesiology, Department of Pathology and Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Pediatrics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ouyang
authors.affiliation: Department of Anesthesiology, Department of Pathology and Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.
authors.forename: Huawei
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.
authors.forename: Fan
authors.initials: F
authors.lastname: Xing
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.
authors.forename: Jialuo
authors.initials: J
authors.lastname: Mai
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.
authors.forename: Bingzheng
authors.initials: B
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.|South China Sea Bio-Resource Exploitation and Utilization Collaborative Innovation Center and Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China.
authors.forename: Guangmei
authors.initials: G
authors.lastname: Yan
authors.affiliation: Department of Anesthesiology, Stony Brook University Health Science Center, Stony Brook, NY, 11794-8480, USA. jun.lin@stonybrookmedicine.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China. zhuwenbo@mail.sysu.edu.cn.|South China Sea Bio-Resource Exploitation and Utilization Collaborative Innovation Center and Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China. zhuwenbo@mail.sysu.edu.cn.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhu
mesh_terms: D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D057225:Data Mining; D016208:Databases, Factual; D005455:Fluorescent Antibody Technique; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008874:Midazolam / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D014151:Anti-Anxiety Agents; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050053:TRPM Cation Channels; D017346:Protein Serine-Threonine Kinases; C486583:TRPM7 protein, human; D008874:Midazolam; D002118:Calcium
keywords: Calcium; Cell cycle arrest; Glioma proliferation; Midazolam; TRPM7