NDLI: Functional cooperativity by direct interaction between PAK4 and MMP-2 in the regulation of anoikis resistance, migration and invasion in glioma.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Kesanakurti, D. Chetty, C. Rajasekhar Maddirela, D. Gujrati, M. Rao, J. S.
Description	Country affiliation: United States Author Affiliation: Kesanakurti D ( Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, IL 61605, USA.)
Abstract	Gliomas display anoikis resistance, enhanced invasion in to the adjacent brain parenchyma and eventually recur despite using the standard therapies. Our studies on increased anoikis sensitization in matrix metalloproteinase-2 (MMP-2)-knockdown 4910 and 5310 human glioma xenograft cells were interestingly correlated with p21-activated kinase 4 (PAK4) inhibition, prompting us to further investigate the role of PAK4 in glioma. Here, we report the PAK4 upregulation in positive correlation with increasing glioma pathological grades. The siRNA-mediated PAK4 knockdown elevated anoikis, and inhibited invasion and migration by downregulating MMP-2, vß3-integrin and phospho-epidermal growth factor receptor (phospho-EGFR). The cDNA-PCR arrays revealed a transcriptional suppression of essential proteins involved in cell proliferation and adhesion in PAK4-knockdown cells. Most importantly, glutathione S-transferase pull-down assays demonstrated the MMP-2 as a new PAK4-interacting protein which binds to PAK4 kinase domain. Individual EGFR/ErbB2 inhibitor and vß3 antibody treatments in PAK4si-treated cells indicated the regulation of vß3/EGFR survival signaling by PAK4. Overexpression of PAK4 significantly reversed the MMP2si-induced cell death in both cell lines. Codepletion of PAK4 and MMP-2 resulted in robust anoikis-mediated cell death, and severely inhibited invasive and migratory properties in these cells. PAK4si inhibited in vivo tumor growth in nude mice by inhibiting MMP-2, ß3-integrin and phospho-EGFR levels in tumors. Our findings indicate a physical association between PAK4 and MMP-2, and suggest the future therapeutic potential of PAK4/MMP-2 dual targeting in glioma treatment.
File Format	HTM / HTML
e-ISSN	20414889
DOI	10.1038/cddis.2012.182
Journal	Cell Death and Disease
Volume Number	3
Language	English
Publisher	Nature Publishing Group
Publisher Date	2012-12-20
Publisher Place	Great Britain (UK)
Access Restriction	Open
Subject Keyword	Research Support, N.i.h., Extramural P21-activated Kinases Signal Transduction Neoplasm Invasiveness Matrix Metalloproteinase 2 Transplantation, Heterologous Metabolism Physiopathology Integrin Alphavbeta3 Discipline Cell Biology Pathology Animals Glioma Mice, Nude Cell Line, Tumor Protein Binding Anoikis Genetics Mice Cell Movement Receptor, Epidermal Growth Factor
Content Type	Text
Resource Type	Article

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