title: Inhibition of TRPM7 by carvacrol suppresses glioblastoma cell proliferation, migration and invasion.
abstract: Glioblastomas are progressive brain tumors with devastating proliferative and invasive characteristics. Ion channels are the second largest target class for drug development. In this study, we investigated the effects of the TRPM7 inhibitor carvacrol on the viability, resistance to apoptosis, migration, and invasiveness of the human U87 glioblastoma cell line.The expression levels of TRPM7 mRNA and protein in U87 cells were detected by RT-PCR, western blotting and immunofluorescence. TRPM7 currents were recorded using whole-cell patch-clamp techniques. An MTT assay was used to assess cell viability and proliferation. Wound healing and transwell experiments were used to evaluate cell migration and invasion. Protein levels of p-Akt/t-Akt, p-ERK1/2/t-ERK1/2, cleaved caspase-3, MMP-2 and phosphorylated cofilin were also detected.TRPM7 mRNA and protein expression in U87 cells is higher than in normal human astrocytes. Whole-cell patch-clamp recording showed that carvacrol blocks recombinant TRPM7 current in HEK293 cells and endogenous TRPM7-like current in U87 cells. Carvacrol treatment reduced the viability, migration and invasion of U87 cells. Carvacrol also decreased MMP-2 protein expression and promoted the phosphorylation of cofilin. Furthermore, carvacrol inhibited the Ras/MEK/MAPK and PI3K/Akt signaling pathways.Therefore, carvacrol may have therapeutic potential for the treatment of glioblastomas through its inhibition of TRPM7 channels.
authors.affiliation: Department of Surgery, University of Toronto, Toronto, Canada.|Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Chen
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Barszczyk
authors.affiliation: Department of Surgery, University of Toronto, Toronto, Canada.|Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Turlova
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: Marielle
authors.initials: M
authors.lastname: Deurloo
authors.affiliation: Department of Surgery, University of Toronto, Toronto, Canada.|Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: Baosong
authors.initials: B
authors.lastname: Liu
authors.affiliation: Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
authors.forename: Burton B
authors.initials: BB
authors.lastname: Yang
authors.affiliation: Department of Surgery, University of Toronto, Toronto, Canada.
authors.forename: James T
authors.initials: JT
authors.lastname: Rutka
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: Zhong-Ping
authors.initials: ZP
authors.lastname: Feng
authors.affiliation: Department of Surgery, University of Toronto, Toronto, Canada.|Department of Physiology, University of Toronto, Toronto, Canada.|Department of Pharmacology, University of Toronto, Toronto, Canada.|Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Canada.
authors.forename: Hong-Shuo
authors.initials: HS
authors.lastname: Sun
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D000081007:Cymenes; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D039821:Monoterpenes / Q000494:pharmacology*; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D051339:Actin Depolymerizing Factors; D000970:Antineoplastic Agents; D000081007:Cymenes; D039821:Monoterpenes; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050053:TRPM Cation Channels; C073316:carvacrol; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C486583:TRPM7 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
keywords: TRPM7; carvacrol; cell viability; glioblastoma; invasion; migration