Signals from the extracellular matrix are essential for cell survival. The disruption of these signals induces cell death in many cell types. The small GTPases of the Rho family, which is involved in cell proliferation, differentiation and motility, also control anoikis, one of the signaling pathways involved in apoptosis. Matrix metalloproteinase-2 (MMP-2; also known as gelatinase A) is known to play a role in tumor invasion, metastasis and angiogenesis. Here, we show that siRNA-based downregulation of MMP-2 induced apoptosis in U87 and U251 glioblastoma cell lines as determined by TUNEL assay. As determined by GST-pull down assay, MMP-2 inhibition altered cytoskeletal organization and inhibited the GTP-bound forms of Rac1 and Cdc42. Furthermore, downregulation of MMP-2 induced the activation of the MEK-ERK signaling cascade. Specific inhibitors of the MEK pathway, U0126 and PD98059, inhibited MMP-2 siRNA-induced apoptosis and phosphorylation as well as the nuclear translocation of ERK. In summary, our data demonstrate that the inhibition of MMP-2 induces apoptotic signaling through MEK-ERK in U87 and U251 glioblastoma cell lines.
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1462.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO