Abstract A4: Guanylate binding protein-1 promotes glioma cell invasion through induction of MMP1 expression

Abstract

Abstract Glioma is the most common and deadly human brain tumor. Epidermal growth factor receptor (EGFR) amplification or constitutively active mutation (EGFRVIII) is one of the most frequent genetic lesions in gliomas. To identify target genes regulated by EGFR signaling, we performed expression array analysis and found that human guanylate binding protein-1 (GBP-1), a large GTPase that is induced by inflammatory cytokines, is one of the predominant genes induced by EGFR/EGF or EGFR VIII kinase activity. Our results demonstrate that EGF/EGFR signaling could dramatically induce Gbp-1 expression at both the mRNA and protein level through the p38 kinase signaling cascade that is distinct from Stat1 signaling used by interferon gamma. Interestingly, we show that Gbp-1 is required for EGFR-mediated matrix metallopeptidase-1 (MMP1) expression, and plays a role in glioma cell invasion in vitro. Overexpression of Gbp-1 induced MMP1 expression in glioma cells, which was independent of Gbp-1 GTPase activity. In contrast, siRNA-mediated knockdown of Gbp-1 inhibited MMP1 expression and in turn blocked cell invasion as well. Consistently, we found that GBP-1 is overexpressed and positively correlated with EGFR/EGFRVIII and MMP1 expression in human glioma clinical samples and glioma cell lines. Therefore, this study suggests that Gbp-1 may be a novel therapeutic target in glioma. Citation Information: Cancer Res 2009;69(23 Suppl):A4.