MMP-2 plays a key role in the degradation of the extracellular matrix and thereby enhances the proliferative, invasive and metastatic potential of cancer cells. MMP-2 knockdown using siRNA (pM) in human glioma xenograft cell lines, 4910 and 5310, sensitized cells to anoikis associated with cleavage of PARP, and caspases 8 and 3. pM-inhibited cell adhesion, invasion and migration correlated with attenuation of EGFR, c-Src and Pak4 phosphorylation. High expression of Pak4 in human glioma cell lines and tumor tissues implicated its essential role in increasing glioma malignancy. Co-immunoprecipitation studies implied that MMP-2 directly interacts by complex formation with EGFR, p130CAS and Pak4 along with αvβ3 integrin and pM treatment disrupted this direct binding. Vitronectin-mediated αvβ3 activation and EGF and rhMMP-2 supplementation counteracted pM-inhibited, Pak4-mediated migration and invasion. Conversely, αvβ3 blocking antibody and ErbB-2/EGFR inhibitor (GW2974) further reduced pM-inhibited, Pak4-mediated invasiveness and migration, thereby suggesting a role of αvβ3 and EGFR in the regulation of Pak4 survival signaling. Individual treatments of pM and Pak4.si led to considerable anoikis in both 4910 and 5310 cells and simultaneous co-depletion MMP-2 and Pak4 resulted in robust increase in anoikis levels. In vivo orthotopic experiments in nude mice revealed decreased tumor size with pM treatment. Immunofluorescence analysis of pSV-tumor sections showed high expression and co-localization of MMP-2/αvβ3, which decreased upon treatment with pM along with significant decrease in phospho-EGFR, phospho-Pak4, Bcl2 and Bcl-xL levels. Our results imply a possible crosstalk between MMP-2 and Pak4 and suggest the potential of targeting both MMP-2 and Pak4 as a future therapeutic approach in glioma therapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2085. doi:1538-7445.AM2012-2085

©2012 American Association for Cancer Research
2012