Protein kinase C-alpha activation by phorbol ester induces secretion of gelatinase B/MMP-9 through ERK 1/2 pathway in capillary endothelial cells.
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-alpha inhibitor, and introduction of antisense PKC-alpha into these cells reduced the secretion of MMP-9 and activation of ERK1/2 by PMA. Furthermore, we employed adenoviral PKC-alpha 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-alpha, partly at least, have a crucial role in MMP-9 secretion and invasion of BCE cells which are mediated via ERK1/2 signaling pathway.
Park
Myung-Jin
MJ
Laboratory of Cell Biology, Korea Cancer Center Hospital, 139-706 Seoul, Korea.
Park
In-Chul
IC
Lee
Hyung-Chan
HC
Woo
Sang-Hyeok
SH
Lee
Jae-Young
JY
Hong
Young-Joon
YJ
Rhee
Chang-Hun
CH
Lee
Yun-Sil
YS
Lee
Seung-Hoon
SH
Shim
Bum-Sang
BS
Kuroki
Toshino
T
Hong
Seok-Il
SI
D000818:Animals; D002196:Capillaries / Q000166:cytology / Q000201:enzymology; D002417:Cattle; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology*; D004789:Enzyme Activation; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology*; D051571:Protein Kinase C-alpha; D011725:Pyridines / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D005419:Flavonoids; D007093:Imidazoles; D011725:Pyridines; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one