Expression of collagenase-3 (MMP-13) and collagenase-1 (MMP-1) by transformed keratinocytes is dependent on the activity of p38 mitogen-activated protein kinase

Collagenase-3 (MMP-13) is a human matrix metalloproteinase specifically exp ressed by transformed squamous epithelial cells, i.e. squamous cell carcino ma (SCC) cells in culture and in vivo, Here, we have elucidated the signali ng pathways regulating MMP-13 expression in transformed human epidermal ker atinocytes, i.e. ras-transformed HaCaT cell line A-5 and cutaneous SCC cell line (UT-SCC-7). Treatment with tumor necrosis factor-alpha (TNF-) resulte d in activation of extracellular signal-regulated kinase (ERK)1,2, Jun N-te rminal kinase and p38 mitogen-activated protein kinase (MAPK) in both cell lines, In addition, transforming growth factor-beta (TGF-beta) activated p3 8 MAPK in both cell lines, and ERK2 in A-5 cells, Selective inhibition of p 38 activity with SE 203580 abolished the enhancement of MMP-13, as well as collagenase-1 (MMP-1) and 92-kDa gelatinase (MMP-9) expression by TNF-alpha and TGF-beta, Blocking the ERK1,2 pathway by PD 98059 had no effect on the induction of MMP-13 expression by TNF-alpha or TGF-beta, but potently supp ressed MMP-1 and MMP-9 production, Inhibition of p38 activity by SE 203580 also suppressed collagenolytic activity produced by both cell lines and inh ibited invasion of TNF-alpha or TGF-beta stimulated A-5 cells through type I collagen and reconstituted basement membrane (Matrigel). These results sh ow that activation of p38 MAPK pathway plays a crucial role in the invasive phenotype of transformed squamous epithelial cells, suggesting p38 MAPK as a target to specifically inhibit their invasion.