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 expressed by transformed squamous epithelial cells, i.e. squamous cell carcinoma (SCC) cells in culture and in vivo, Here, we have elucidated the signaling pathways regulating MMP-13 expression in transformed human epidermal keratinocytes, i.e. ras-transformed HaCaT cell line A-5 and cutaneous SCC cell line (UT-SCC-7). Treatment with tumor necrosis factor-alpha (TNF-) resulted in activation of extracellular signal-regulated kinase (ERK)1,2, Jun N-terminal kinase and p38 mitogen-activated protein kinase (MAPK) in both cell lines, In addition, transforming growth factor-beta (TGF-beta) activated p38 MAPK in both cell lines, and ERK2 in A-5 cells, Selective inhibition of p38 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 suppressed MMP-1 and MMP-9 production, Inhibition of p38 activity by SE 203580 also suppressed collagenolytic activity produced by both cell lines and inhibited invasion of TNF-alpha or TGF-beta stimulated A-5 cells through type I collagen and reconstituted basement membrane (Matrigel). These results show 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.