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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A2(PLA2；EC 3.1.1.4)催化甘油磷脂中sn-2-酰基酯键的水解，释放游离脂肪酸和溶血磷脂。哺乳动物细胞外磷脂酶A_2的分子量为14 kDa，根据其一级结构可分为两类，分别命名为组I(PLA2-I)和组II(PLA2-II)。PLA2-II存在于某些炎症区的细胞外间隙，可刺激多种细胞和组织产生前列腺素D2和E2，提示PLA2-II可能在炎症性疾病的发病机制中起重要作用。由胰腺腺泡细胞分泌的PLA2-I是一种非活性酶原，经胰酶消化后起到消化脂肪酸的作用。最近的研究表明，磷脂酶A_2-I不仅存在于胰腺中，而且还存在于肺、脾等非消化器官中，提示磷脂酶A_2-I除了作为消化酶外，还可能具有一定的作用。我们发现，人胰腺磷脂酶A_2组I(hPLA2-I)诱导人胰腺癌细胞MIAPaCa-2的生长是通过其受体介导的，而不是通过其催化性质实现的。本研究表明MIAPaCa-2细胞中丝裂原活化蛋白激酶(MAPK)级联通路的激活是由hPLA2-I诱导的：该消化酶可诱导MEK1/2、p44/42 MAPK和ATF-2的磷酸化，而与MEK选择性抑制剂PD98059共同孵育后，MAPK级联中的磷酸化被抑制。此外，该抑制剂呈剂量依赖性地阻断hPLA2-I诱导的MIAPaCa-2增殖，提示MAPK通路的激活在hPLA2-I诱导的MIAPaCa-2增殖中起重要作用。