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Involvement of 85-kd cytosolic phospholipase A 2 and cyclooxygenase-2 in the proliferation of human cholangiocarcinoma cells

2002; Lippincott Williams & Wilkins; Volume: 36; Issue: 2 Linguagem: Inglês

10.1053/jhep.2002.34743

1527-3350

Tong Wu, Chang Han, John G. Lunz, George K. Michalopoulos, James H. Shelhamer, Jake Demetris,

PI3K/AKT/mTOR signaling in cancer

Cyclooxygenase 2 (COX-2) and cytosolic phospholipase A 2 (cPLA 2 ) are the crucial rate-limiting enzymes in prostaglandin (PG) metabolism that show increased expression in a number of human cancers, including cholangiocarcinomas; and treatment of cholangiocarcinoma cell lines with COX-2 inhibitors can decrease proliferation. Cholangiocarcinomas also produce and proliferate in response to nonneoplastic biliary epithelial cell mitogens, such as interleukin 6 (IL-6) and hepatocyte growth factor (HGF). This study was designed to determine whether there is any relationship between eicosanoid metabolism and growth stimulation by IL-6 and HGF, two important biliary epithelial cell and cholangiocarcinoma mitogens. Incubation of SG231, a well-characterized human cholangiocarcinoma cell line, with HGF, IL-6, PGE 2 , or PGF 2 α resulted in significantly increased cell growth. HGF and IL-6 also induced a rapid release of arachidonic acid (AA) from SG231 and increased the synthesis of PGE 2 and PGF 2 α. The cPLA 2 inhibitor arachidonyl fluorophosphonate (MAFP) and the COX-2 inhibitor NS-398 significantly inhibited HGF- and IL-6-induced release of AA, PG synthesis, and proliferation in SG231 cells as well as two other human cholangiocarcinoma cell lines, HuCCT1 and CC-LP-1 cells. Thus, PGs alone can induce cholangiocarcinoma growth, and the HGF- and IL-6-induced proliferation is mediated, at least in part, by PGs. HGF and IL-6 also induced a rapid phosphorylation of cPLA 2 (within 1 minute) but did not alter cPLA 2 and COX-2 protein expression. The HGF- and IL-6-induced cPLA 2 phosphorylation was blocked by the inhibitors of p38 and p42/44 MAP kinases, protein kinase C, calmodulin kinase, and tyrosine kinase, showing that HGF- and IL-6-induced AA release and PG production are mediated by phosphorylation of cPLA 2 . In conclusion, molecular pathways link classic biliary epithelial cell mitogens to PG metabolism constituents in cholangiocarcinoma growth, which may be exploited as potential therapeutic targets.