title: Amsacrine suppresses matrix metalloproteinase-2 (MMP-2)/MMP-9 expression in human leukemia cells.
abstract: This study explores the suppression mechanism of amsacrine (4-(9-Acridinylamino)-N-(methanesulfonyl)-m-anisidine hydrochloride) on matrix metalloproteinase-2 (MMP-2) and MMP-9 expression in human leukemia cells. Amsacrine attenuated cell invasion with decreased MMP-2/MMP-9 protein expression and mRNA levels in U937, Jurkat, HL-60, K562, KU812, and MEG-01 cells. Moreover, amsacrine reduced both MMP-2/MMP-9 promoter luciferase activity and MMP-2/MMP-9 mRNA stability in leukemia cells. Studies on amsacrine-treated U937 cells revealed that amsacrine-elicited ROS generation induced JNK and p38 MAPK activation but reduced the phospho-ERK level. Amsacrine-induced ERK inactivation and p38 MAPK/JNK activation were demonstrated to suppress MMP-2/MMP-9 promoter luciferase activity and promote MMP-2/MMP-9 mRNA decay, respectively. p38 MAPK/JNK activation led to up-regulation of protein phosphatase 2A catalytic subunit α (PP2Acα) in amsacrine-treated U937 cells. Okadaic acid (PP2A inhibitor) treatment increased MMP-2/MMP-9 mRNA stability in amsacrine-treated cells, whereas PP2Acα over-expression increased MMP-2/MMP-9 mRNA decay. Amsacrine-induced MMP-2/MMP-9 down-regulation was also related to PP2Acα up-regulation on Jurkat, HL-60, K562, KU812, and MEG-01 cells. Collectively, our data indicate that amsacrine induces MMP-2/MMP-9 down-regulation via simultaneous suppression of genetic transcription and mRNA stability in human leukemia cells.
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
authors.forename: Wen-Hsin
authors.initials: WH
authors.lastname: Liu
authors.forename: Ying-Jung
authors.initials: YJ
authors.lastname: Chen
authors.forename: Jen-Hung
authors.initials: JH
authors.lastname: Chien
authors.forename: Long-Sen
authors.initials: LS
authors.lastname: Chang
mesh_terms: D000677:Amsacrine / Q000737:chemistry / Q000494:pharmacology*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007938:Leukemia / Q000201:enzymology*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D015394:Molecular Structure; D054648:Protein Phosphatase 2 / Q000145:classification / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020298:U937 Cells; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D000677:Amsacrine; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D054648:Protein Phosphatase 2; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9