Gallic acid downregulates matrix metalloproteinase‐2 (MMP‐2) and MMP‐9 in human leukemia cells with expressed Bcr/Abl

Abstract

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. 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. 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.