title: Connexin-43 regulates p38-mediated cell migration and invasion induced selectively in tumour cells by low doses of γ-radiation in an ERK-1/2-independent manner.
abstract: Radiotherapy exposes certain regions of solid tumours to low sublethal doses of γ-radiation that may cause secondary malignancies. Therefore, evaluating low-dose-γ-radiation-induced alterations in tumorigenic potential and understanding their mechanisms could help in improving radiotherapy outcome. Limited studies have indicated connexin (Cx) up-regulation by low doses, whereas Cxs are independently shown to alter cell migration in unirradiated cells. We investigated low-dose-γ-radiation-induced alterations in Cx43 expression and cell proliferation/migration/invasion in various tumour cell lines, along with the putative molecular pathways such as p38 and extracellular signal-regulated kinase-1/2 (ERK-1/2)-mitogen-activated protein kinases (MAPKs). Interestingly, a narrow range of low doses (10-20 cGy) enhanced Cx43 expression and also selectively induced glioma cell migration without altering cell proliferation, accompanied by sustained activation of p38 and up-regulation of p21(waf1/cip1), whereas the lowest (5 cGy) dose induced cell proliferation coupled with enhanced p-ERK1/2, proliferating cell nuclear antigen and p-H3 levels without inducing cell migration. Most importantly, low-dose-γ-radiation-induced cell migration and p38 activation was strongly inhibited by knocking down Cx43 expression, thereby demonstrating latter's upstream role, whereas the knock-down had no effect on ERK-1/2 or cell proliferation. Silencing Cx43 caused near-complete inhibition of radiation-induced cell migration/invasion in all tumour cell lines (U87, BMG-1, A549 and HeLa), whereas no cell migration/invasiveness was induced in the γ-irradiated primary VH10 or transformed AA8 fibroblasts. Our study demonstrates for the first time that low-dose γ-radiation induces p38-MAPK mediated cell migration selectively in tumour cells. Further, this effect is regulated by Cx43, which could thus be an important mediator in radiation-induced secondary malignancies and/or metastasis.
authors.affiliation: Natural Radiation Response Mechanisms Group, Division of Radiation Biosciences with.
authors.forename: Soma
authors.initials: S
authors.lastname: Ghosh
authors.forename: Ashish
authors.initials: A
authors.lastname: Kumar
authors.forename: Rajendra Prashad
authors.initials: RP
authors.lastname: Tripathi
authors.forename: Sudhir
authors.initials: S
authors.lastname: Chandna
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D018031:Connexin 43 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004307:Dose-Response Relationship, Radiation; D005720:Gamma Rays; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018031:Connexin 43; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases