title: Restoration of IRF1-dependent anticancer effects by MEK inhibition in human cancer cells.
abstract: Interferon regulatory factor (IRF1) is a potent antiviral, antitumor and immune regulatory protein. Recently, we found that activated Ras/MEK inhibits antiviral response by downregulating IRF1 expression and renders cancer cells susceptible to oncolytic viruses. In this study, we sought to determine whether IRF1 downregulation underlies oncogenesis induced by Ras/MEK activation in human cancer cells. Treatment of the MEK inhibitor U0126 promoted IRF1 expression in 7 of 11 cancer cell lines we tested. IRF1 promotion was also observed in human cancer cell lines treated with different MEK inhibitors or with RNAi oligonucleotides against extracellular signal-regulated kinases (ERKs). Restoration of the expression of antitumor genes, p27 and p53 upregulated modulator of apoptosis (PUMA), by MEK inhibition was less in IRF1 shRNA knockdown cancer cells than in vector control cancer cells, suggesting that Ras/MEK targets IRF1 for the downregulation of the antitumor genes. Moreover, apoptosis induction by U0126 was significantly reduced in IRF1 shRNA knockdown cells than vector control cells. This study demonstrates that IRF1 expression is suppressed by activated Ras/MEK in human cancer cells and that IRF1 plays essential roles in apoptosis induced by Ras/MEK inhibition.
authors.affiliation: Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
authors.forename: Nader
authors.initials: N
authors.lastname: AbuSara
authors.affiliation: Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
authors.forename: Seyd
authors.initials: S
authors.lastname: Razavi
authors.affiliation: Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
authors.forename: Leena
authors.initials: L
authors.lastname: Derwish
authors.affiliation: Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Komatsu
authors.affiliation: Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
authors.forename: Maria
authors.initials: M
authors.lastname: Licursi
authors.affiliation: Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada. Electronic address: kensuke@mun.ca.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Hirasawa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics* / Q000378:metabolism; D061986:MCF-7 Cells; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D002070:Butadienes; D004791:Enzyme Inhibitors; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D009570:Nitriles; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C113580:U 0126; D050760:Cyclin-Dependent Kinase Inhibitor p27; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018631:ras Proteins
keywords: Apoptosis; Interferon regulatory factor (IRF1); Ras/MEK