MMP-2 downregulation mediates differential regulation of cell death via ErbB-2 in glioma xenografts.

The epidermal growth factor receptor (EGFR) family (also known as the ErbB protein family) is comprised of four structurally-related receptor tyrosine kinases. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's disease. In contrast, excessive ErbB signaling is associated with the development of a wide variety of solid tumors. ErbB-1 and -2 are found in many human cancers and their excessive signaling may be critical factors in the development and malignancy of solid tumors. Several molecular strategies have been developed recently to modulate either EGFR or the downstream signal beyond the cell surface receptor. In the present study, we used human EGFR-overexpressing glioma xenograft cells 4910 and 5310 and targeted MMP-2 expression using an adenoviral RNAi construct. We observed that the RNAi-mediated downregulation of MMP-2 causes the upregulation of ErbB-2 in certain EGFR-overexpressing glioma xenograft cells both in vitro and in vivo. Targeted MMP-2 downregulation was observed in a dose-dependent manner with no apparent off-target effects in these xenograft cells. We also noted that the overexpression of ErbB-2 induced by MMP-2 downregulation is consistent with p50-mediated cell death in 5310 cells but not in 4910 cells. In addition, APAF-1 expression levels increased in correlation with increased ErbB-2 expression after MMP-2 downregulation in vitro and in vivo. Our results suggest that MMP-2 may play a role in a hitherto unknown signaling pathway mediated via ErbB-2 in certain cancer cell types.