14707447

pubmed:Citation

4

Pancreatic carcinoma is characterized by poor prognosis and lack of response to conventional therapy. The reasons for this are not fully understood. We have reported that inhibition of 5-lipoxygenase abolished proliferation and induced apoptosis in pancreatic cancer cells while the 5-lipoxygenase metabolite, 5(S)-hydroxyeicosatetraenoic acid [5(S)-HETE] stimulated pancreatic cancer cell proliferation. The current study was designed to investigate the underlying mechanisms for 5(S)-HETE-stimulated proliferation of pancreatic cells. Two human pancreatic cancer cell lines, PANC-1 and HPAF, were used. Cell proliferation was monitored by thymidine incorporation and cell counting. Phosphorylation of P42/44(MAPK) (mitogen activated protein kinase, ERK), MEK (MAPK/ERK kinase), P38 kinase, JNK/SAPK (c-Jun N-terminal kinase/ stress-activated protein kinase), AKT and tyrosine residues of intracellular proteins was measured by Western blot using their corresponding phospho-specific antibodies. The results showed that (1) 5(S)-HETE markedly stimulated pancreatic cancer cell proliferation in a time- and concentration-dependent manner; (2) 5(S)-HETE induced tyrosine phosphorylation of multiple intracellular proteins while the tyrosine kinase inhibitor, genestein, blocked 5(S)-HETE-stimulated cell proliferation; (3) 5(S)-HETE significantly stimulated both MEK and P42/44(MAPK) phosphorylation and the MEK inhibitors, PD098059 and U0126, inhibited 5(S)-HETE-stimulated proliferation in these two cell lines; (4) 5(S)-HETE also stimulated P38 kinase phosphorylation but the P38 inhibitor, SB203580, did not effect 5(S)-HETE-stimulated cell proliferation; (5) 5(S)-HETE markedly stimulated AKT phosphorylation while the phosphatidylinositide-3 (PI3)-kinase inhibitor, wortmannin, blocked 5(S)-HETE-stimulated cell proliferation; (6) phosphorylation of JNK/SAPK was not induced by 5(S)-HETE, and (7) the general protein kinase C (PKC) inhibitor, GF109203X, did not affect 5(S)-HETE-stimulated cancer cell proliferation. These findings suggest that intracellular tyrosine kinases, MEK/ERK and PI3 kinase/AKT pathways are involved in 5(S)-HETE-stimulated pancreatic cancer cell proliferation but P38 kinase, JNK/SAPK and PKC are not involved in this mitogenic effect.

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pubmed-author:AdrianThomas ETE, pubmed-author:DingXian-ZhongXZ, pubmed-author:TongWei-GangWG

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285-94

pubmed-meshheading:14707447-Arachidonate 5-Lipoxygenase, pubmed-meshheading:14707447-Cell Line, Tumor, pubmed-meshheading:14707447-DNA, Neoplasm, pubmed-meshheading:14707447-Enzyme Activation, pubmed-meshheading:14707447-Humans, pubmed-meshheading:14707447-Hydroxyeicosatetraenoic Acids, pubmed-meshheading:14707447-MAP Kinase Kinase Kinase 1, pubmed-meshheading:14707447-MAP Kinase Kinase Kinases, pubmed-meshheading:14707447-MAP Kinase Signaling System, pubmed-meshheading:14707447-Mitogen-Activated Protein Kinase 1, pubmed-meshheading:14707447-Mitogen-Activated Protein Kinase 3, pubmed-meshheading:14707447-Mitogen-Activated Protein Kinases, pubmed-meshheading:14707447-Pancreatic Neoplasms, pubmed-meshheading:14707447-Phosphatidylinositol 3-Kinases, pubmed-meshheading:14707447-Phosphorylation, pubmed-meshheading:14707447-Protein-Serine-Threonine Kinases, pubmed-meshheading:14707447-Protein-Tyrosine Kinases, pubmed-meshheading:14707447-Proto-Oncogene Proteins, pubmed-meshheading:14707447-Proto-Oncogene Proteins c-akt, pubmed-meshheading:14707447-Time Factors, pubmed-meshheading:14707447-Tumor Cells, Cultured

Multiple signal pathways are involved in the mitogenic effect of 5(S)-HETE in human pancreatic cancer.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't