Protein kinase C-α activation by phorbol ester induces secretion of gelatinase B/MMP-9 through ERK 1/2 pathway in capillary endothelial cells

Abstract

In the present study, phorbol 12-myristate 13-acetate (PMA) was found to increase secretion of matrix metalloproteinase (MMP)-9 and in vitro invasion in bovine capillary endothelial (BCE) cells, which were blocked by specific inhibitors of protein kinase C (PKC). To elucidate molecular mechanisms involved, we studied the effect of PMA on the activation of mitogen activated protein kinases (MAPKs), and found that PMA activated extracellular signal-regulated kinase (ERK)1/2 and PD98059, a specific inhibitor of MAPK kinase, significantly reduced PMA-induced MMP-9 secretion as well as in vitro invasion of BCE cells. Treatment of safingol, a specific PKC-α inhibitor, and introduction of antisense PKC-α into these cells reduced the secretion of MMP-9 and activation of ERK1/2 by PMA. Furthermore, we employed adenoviral PKC-α and found that weak PMA stimulation (5 ng/ml) enhanced ERK1/2 activation and MMP-9 secretion in these cells. Therefore, we strongly suggest that PKC-α, partly at least, have a crucial role in MMP-9 secretion and invasion of BCE cells which are mediated via ERK1/2 signaling pathway.