Abstract A8: Vasodilator-stimulated phosphoprotein Ser239 regulates matrix metalloproteinase-9 in colon cancer

Cancer invasion and spreading is promoted by membrane protrusion formation driven by actin polymerization and filament (F)-actin elongation, a process controlled by the actin-binding protein vasodilator-stimulated phosphoprotein (VASP). Tumor epithelial cell matrix metalloproteinase-9 (MMP-9) is a key promoter of carcinogenesis and invasion in colon cancer. Interestingly, both VASP and MMP-9 activities are regulated by intracellular cGMP signaling in colon cancer cells. However, direct functional relationships between VASP and MMP-9 are unrecognized. Here, human colon carcinoma cells were examined by immunoblotting, sucrose-gradient fractionation, confocal microscopy and imaging analysis. MMP-9 localizes at membrane protrusions and lipid rafts, cell surface microdomains specialized in signal transduction, in a cGMP-dependent manner. Activation of cGMP signaling disrupted membrane protrusion dynamics and induced intracellular MMP-9 redistribution. Strikingly, cancer cells expressing the serine-to-alanine VASP phosphomutant at Ser239, resistant to cGMP-dependent VASP phosphorylation, were insensitive to cGMP effects on membrane protrusions and MMP-9. Importantly, cGMP signaling through VASP Ser239, but not Ser157, critically regulates the ability of cancer cells to release MMP-9 in the extracellular environment. Together, these observations indicate tumor epithelial cell MMP-9, a key promoter of cancer invasion, is regulated by VASP Ser239 phosphorylation, a previously unappreciated paradigm in colon cancer biology. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A8.