title: MiR-92a mediates AZD6244 induced apoptosis and G1-phase arrest of lymphoma cells by targeting Bim.
abstract: AZD6244, an ATP-uncompetitive inhibitor of mitogen-activated protein kinase 1/2 (MEK1/2), has shown activity in several malignant tumours. However, whether AZD6244 has a function in lymphoma cells is not known. We report that AZD6244 treatment represses the growth of Raji and MOLT4 cells by inducing apoptosis and G1-phase arrest. Using miRNAs array and quantitative RT-PCR, miR-92a was downregulated byAZD6244 treatment through the ERK1/2-AP1 signalling pathway. Overexpression of miR-92a abrogated AZD6244-induced apoptosis and G1-phase arrest, indicating that it is involved in the cytotoxicity of AZD6244 in lymphoma cells. A luciferase reporter assay showed that miR-92a directly targetsthe 3'-UTRs of Bim. Overexpression of miR-92a mimics downregulated Bim mRNA and protein expression level, indicating that miR-92a negatively regulates its expression at both levels. Silencing Bim decreases AZD6244-induced apoptosis and G1-phase arrest, suggesting that Bim contributes to the growth arrest. Thus, miR-92a mediates AZD6244-induced cytotoxicity of lymphoma cells by targeting Bim. Downregulation of miR-92a by AZD6244 is mediated by the ERK1/2-AP1 signalling pathway.
authors.affiliation: Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou, P.R. China; Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou, P.R. China.
authors.forename: Xiao-Bin
authors.initials: XB
authors.lastname: Lv
authors.forename: Xing
authors.initials: X
authors.lastname: Zhang
authors.forename: Lan
authors.initials: L
authors.lastname: Deng
authors.forename: Ling
authors.initials: L
authors.lastname: Jiang
authors.forename: Wei
authors.initials: W
authors.lastname: Meng
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Lu
authors.forename: Xiuju
authors.initials: X
authors.lastname: Wang
mesh_terms: D020413:3' Untranslated Regions; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D000072224:Bcl-2-Like Protein 11; D001562:Benzimidazoles / Q000633:toxicity*; D002460:Cell Line; D015536:Down-Regulation; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008223:Lymphoma; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020413:3' Untranslated Regions; C517975:AZD 6244; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D001562:Benzimidazoles; C541874:MIRN92 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: AP1; AZD6244; Bim; MEK1/2; lymphoma; miR-92a