|Budget Amount *help
¥7,700,000 (Direct Cost : ¥7,700,000)
Fiscal Year 1997 : ¥1,900,000 (Direct Cost : ¥1,900,000)
Fiscal Year 1996 : ¥5,800,000 (Direct Cost : ¥5,800,000)
Phospholipase A_2 (PLA_2 ; EC 220.127.116.11) catalyzes the hydrolysis of the sn-2-acyl ester bond in glycerophospholipids to liberate free fatty acids and lysophospholipids. The mammalian extracellularPLA_2s having the molecular weight of 14kDa are classified into two types, designated group I (PLA_2-I) and group II (PLA_2-II), based on their primary structures. PLA_2-II,found in the extracellular spaces of some inflammatory regions, stimulates production of prostaglandin D2 and E2 in several cells and tissues, suggesting that PLA_2-II may play in important role in the pathogenesis of inflammatory diseases.
PLA2-I,secreted from pancreatic acinar cells as an inactive zymogen, functions as an enzyme digesting fatty acids after cleavaged with trypsin. Recent studies have shown that PLA_2-Iexists not only in the pancreas, but also in non-digestive organ such as lung or spleen, sugesting that PLA_2 -I might have some function except that as the digestive enzyme.
We have found that the growth of human pancreatic cancer cells MIAPaCa-2, induced by human pancreatic phospholipase A_2 group I (hPLA_2-I), is mediated via its receptor but not kia its catalytic property. The present study showed that activation of mitogen-activated protein kinase (MAPK) cascade in MIAPaCa-2 cells is induced by hPLA_2-I : this digestive enzyme induced phosphorylation of MEK1/2, p44/42 MAPK and ATF-2, and the phosphorylation in MAPK cascade was inhibited after the cells were pri-incubated with a selective inhibitor of MEK,PD98059. In addition, this inhibitor dose-dependently blocked the hPLA_2-I induced MIAPaCa-2 proliferation, suggesting that activation of the MAPK cascade is essential for the hPLA_2-I-induced MIAPaCa-2 proliferation.