Molecular mechanism of proliferation of human pancreatic cancer cells induced by human pancreatic phospholipase A_2

人胰腺磷脂酶A_2诱导人胰腺癌细胞增殖的分子机制

基本信息

批准号：
08457608
负责人：
SUGIYAMA Masanori
金额：
$ 4.93万
依托单位：
HIROSHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08457608/
关键词：
signal transduction pancreatic juice pancreatic cancer cell proliferation phospholipase A_2 MAPK kinase MARK キナーゼ

项目摘要

Phospholipase A_2 (PLA_2 ; EC 3.1.1.4) 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.

磷脂酶A_2（PLA_2; EC 3.1.1.4）催化甘油磷脂中Sn-2-酰基酯键的水解，以释放游离脂肪酸和溶血磷脂。具有14KDA分子量的哺乳动物细胞外pla_2s分为两种类型，分为两种类型，分别基于其主要结构，分为I组（PLA_2-I）和II组（PLA_2-II）。在某些炎症区域的细胞外空间中发现的PLA_2-II刺激了几个细胞和组织中前列腺素D2和E2的产生，这表明PLA_2-II可能在炎症性疾病的发病机理中起重要作用。用胰蛋白酶切割。 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通过其受体介导，但不能起亚其催化特性。本研究表明，HPLA_2-I诱导有丝分裂原激活的蛋白激酶（MAPK）级联反应：这种消化酶诱导的MEK1/2，p44/42 MAPK和ATF-2的Mek1/2，p44/42的磷酸化，以及MAPK Casecade在MAPK Casecade中的磷酸化磷酸化。 Mek，PD98059。此外，该抑制剂剂量依赖性地阻断了HPLA_2-I诱导的Miapaca-2增殖，这表明MAPK Cascade的激活对于HPLA_2-I-I诱导的Miapaca-2增殖至关重要。