INHIBITION OF THE P38 MITOGEN-ACTIVATED PROTEIN-KINASE BY SB-203580 BLOCKS PMA-INDUCED M-3-92,000 TYPE-IV COLLAGENASE SECRETION AND IN-VITRO INVASION

Although the p38 mitogen-activated protein kinase (MAPK) has been impl icated in signal transduction events, its role in regulating the M-r 9 2,000 type IV collagenase matrix metalloprotease-9 (MMP-9) and in vitr o invasiveness in cancer has not yet been determined. We made the surp rising observation that, in a human squamous cell carcinoma cell line (UM-SCC-1), phorbol ester-enhanced MMP-9 secretion and in vitro invasi veness were associated with a strong activation of the p38 MAPK and it s downstream target, MAPK-activated protein kinase-2. To determine the role of p38 activation in these events, we investigated the effect of SE 203580, a novel specific p38 inhibitor, on protease expression and in vitro invasion of these cells. We found that inhibition of p38 by SE 203580 resulted in the almost complete reduction of phorbol myrista te acetate-induced MMP-9 secretion but not of urokinase-type plasminog en activator secretion. In contrast, the activation of a transiently t ransfected wildtype MMP-9 promoter by MEKK-1, a specific c-Jun NH2-ter minal kinase activator, was only marginally inhibited by the compound, arguing for tbe specificity of SE 203580. Moreover, phorbol myristate acetate-enhanced in vitro invasion was completely blocked by SE 20358 0, whereas p38 inhibition had little effect on growth. These findings suggest that activation of p38 may contribute to a more invasive pheno type in vitro, possibly via the expression of MMP-9, and that targetin g of p38 using SE 203580 may provide a novel means of controlling inva sion of cancers in which this MAPK is activated.