Phosphatidylinositol 3-Kinase and NF-kappaB Involved in Epidermal Growth Factor-Induced Matrix Metalloproteinase-9 Expression

AIM: Matrix metalloproteinase-9 (MMP-9) is a zinc-dependent endopeptidase that is capable of digesting the components of extracellular matrix and basement membrane influencing cancer cell invasion and metastasis. This study is to investigate the signaling pathways responsible for epidermal growth factor (EGF)-induced MMP-9 expression. METHODS: Gelatinase zymography, RT-PCR, and Western blot analysis were exploited to detect the induction of MMP-9 expression in EGF-treated human breast cancer MDA-MB-231 cells. EGF-induced nuclear translocation of EGF receptor (EGFR) and NF-kappaB was demonstrated by immunofluorescence. RESULTS: EGF induced nuclear translocation of EGFR and gene expression of MMP-9 in MDA-MB-231 cells. Phosphorylation of phosphatidylinositol 3-kinase (PI3-K) and nuclear localization of NF-kappaB were also observed with EGF-treated MDA-MB-231 cells. EGF-induced MMP-9 expression was significantly prevented by the inhibitors against PI3-K or NF-kappaB. When MDA-MB-231 cells were treated with curcumin prior to the EGF treatment, cellular EGFR level was drastically reduced and EGF-induced MMP-9 expression was also efficiently prevented. CONCLUSION: EGF induced expression of MMP-9 in MDA-MB-231 cells through the NF-kappaB and PI3-K pathways. Curcumin was able to down regulate cellular EGFR level and inhibit EGF-induced MMP-9 expression.