title: Gallic acid downregulates matrix metalloproteinase-2 (MMP-2) and MMP-9 in human leukemia cells with expressed Bcr/Abl.
abstract: METHODS
  The aim of the present study was to explore the signaling pathways associated with gallic acid induced matrix metalloproteinase-2 (MMP-2)/MMP-9 downregulation in human leukemia K562 cells.
  
  
  RESULTS
  Unlike the insignificant effect on human Bcr/Abl-negative leukemia U937 cells, gallic acid attenuated invasion of human Bcr/Abl-positive leukemia K562 cells with characteristic of decreased protein expression and mRNA levels of MMP-2 and MMP-9. Gallic acid induced β-TrCP upregulation evoked Bcr/Abl degradation in K562 cells, while overexpression of Bcr/Abl attenuated gallic acid induced MMP-2/MMP-9 downregulation. Overexpression of Bcr/Abl restored the levels of phospho-ERK and phospho-Akt but not JNK phosphorylation in gallic acid treated K562 cells. Gallic acid treatment repressed Akt/ERK-mediated c-Fos phosphorylation and JNK1-mediated ATF-2 phosphorylation. c-Jun inactivation was mediated through gallic acid induced Akt/ERK and JNK inactivation. Knockdown of c-Fos, c-Jun, and ATF-2 by siRNA and luciferase promoter assay reflected that c-Jun/ATF-2 and c-Jun/c-Fos were, respectively, responsible for MMP-2 and MMP-9 expression in K562 cells. Chromatin immunoprecipitating assay showed that gallic acid reduced the binding of c-Jun/ATF-2 and c-Jun/c-Fos with promoter region of MMP-2 and MMP-9 genes, respectively.
  
  
  CONCLUSIONS
  Our data indicate that MMP-2 and MMP-9 downregulation in gallic acid treated K562 cells are mediated through suppression of JNK1-mediated c-Jun/ATF-2 and Akt/ERK-mediated c-Jun/c-Fos pathways, respectively.
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
authors.forename: Ying-Jung
authors.initials: YJ
authors.lastname: Chen
authors.forename: Long-Sen
authors.initials: LS
authors.lastname: Chang
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism; D005707:Gallic Acid / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D020014:K562 Cells; D007938:Leukemia / Q000235:genetics / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051698:Activating Transcription Factor 2; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D044844:beta-Transducin Repeat-Containing Proteins; D005707:Gallic Acid; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D048031:JNK Mitogen-Activated Protein Kinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9