FGF-1-induced matrix metalloproteinase-9 expression in breast cancer cells is mediated by increased activities of NF-κB and activating protein-1

✍ Scribed by Gina Lungu; Lina Covaleda; Odete Mendes; Heidi Martini-Stoica; George Stoica

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 365 KB
• Volume: 47
• Category: Article
• ISSN: 0899-1987
• DOI: 10.1002/mc.20398

✦ Synopsis

Abstract

Matrix metalloproteinase‐9 (MMP‐9) plays a critical role in tumor invasion and metastasis. Here, we investigate the effect of fibroblast growth factor‐1 (FGF‐1) on the expression of MMP‐9 in ENU1564, an ethyl‐N‐nitrosourea‐induced rat mammary adenocarcinoma cell line. We observed that FGF‐1 induces a dose‐dependent increase in MMP‐9 mRNA, protein, and activity in ENU1564 cells. To gain insight into the molecular mechanism of MMP‐9 regulation by FGF‐1, we investigated the role of components of PI3K‐Akt and MEK1/2‐ERK signaling pathways in our system since NF‐κB and AP‐1 transcription factor binding sites have been characterized in the upstream region of the MMP‐9 gene. We demonstrated that FGF‐1 increases Akt phosphorylation, triggers nuclear translocation of NF‐κBp65, and enhances degradation of cytoplasmic IκBα. Pretreatment of cells with LY294002, a PI3K inhibitor, significantly inhibited MMP‐9 protein expression in FGF‐1‐treated cells. Conversely, our data show that FGF‐1 increases ERK phosphorylation in ENU1564 cells, increases c‐jun and c‐fos mRNA expression in a time‐dependent manner, and triggers nuclear translocation of c‐jun. Pretreatment of cells with PD98059, a MEK1/2 inhibitor significantly inhibited MMP‐9 protein expression in FGF‐1 treated cells. Finally, we observed increased DNA binding of NF‐κB and AP‐1 in FGF‐1‐treated cells and that mutation of either NF‐κB or AP‐1 response elements prevented MMP‐9 promoter activation by FGF‐1. Taken together, these results demonstrated that FGF‐1‐induced MMP‐9 expression in ENU1564 cells is associated with increasing DNA binding activities of NF‐κB and AP‐1 and involve activation of a dual signaling pathway, PI3K‐Akt and MEK1/2‐ERK. © 2007 Wiley‐Liss, Inc.