| 12-lipoxygenase induces apoptosis of human gastric cancer AGS cells via the ERK1/2 signal pathway. | |
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MedLine Citation:
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PMID: 17522976 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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12-Lipoxygenase (12-LOX) is over-expressed in a variety of human tumors, but its exact effect on the tumorogenesis of gastric cancer remains largely obscure. To investigate the effect of 12-LOX and its inhibitor baicalein on proliferation and apoptosis of human gastric cancer, AGS cells were separately treated with 12-hydroxyeicosatetraenoic acid (12-HETE, a metabolite of 12-LOX) and baicalein. MTT assay revealed that the absorbance of the 12-HETE-treated group was significantly (P < 0.01) higher than that of control group and that the absorbance of baicalein-treated group was significantly (P < 0.01) less than that of the control group, and that 48 h after treatment the apoptosis index of the baicalein-treated group was significantly (P < 0.01) higher than that of the untreated group and was significantly (P < 0.01) lower in the 12-HETE-treated group. Western blotting analysis was used to investigate the mechanism of these effects. The results revealed that the concentration of phosphorylated ERK in cells treated with 100 nmol L(-1) 12-HETE was significantly (P < 0.05) higher than in the untreated group and that the concentration of phosphorylated ERK1/2 in cells treated with 40 micromol L(-1) baicalein was significantly (P < 0.05) lower than in the untreated group. The expression level of bcl-2 was up-regulated and down-regulated after separate treatment with 12-HETE and baicalein, respectively, and both of these effects could be blocked by PD98059. Protein kinase C (PKC) activity was increased by treatment with 12-HETE and reduced by treatment with baicalein (P < 0.05). The PKC inhibitor BIM (bisindolymaleimide-I) blocked the phosphorylation of ERK1/2 and activation of PKC induced by 12-LOX. When pretreated with BIM, the concentration of phospho-ERK1/2 or bcl-2 in the BIM + 12-HETE-treated group was significantly (P < 0.05) lower than in that treated with 12-HETE only, and the concentration in the BIM + baicalein-treated group was significantly (P < 0.05) higher than in that treated with baicalein only. On the basis of these data we conclude that, via its metabolite 12-HETE, 12-LOX abolishes proliferation of AGS cells and protect cells from apoptosis by activating the ERK1/2 pathway and, eventually, enhances expression of bcl-2. Because PKC is also involved in the activation of ERK1/2 induced by 12-LOX, 12-LOX inhibitors would be potentially powerful anticancer agents for prevention and cure of human gastric cancer. |
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Authors:
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Feng-Lin Chen; Xiao-Zhong Wang; Jian-Ying Li; Jie-Ping Yu; Cai-Yun Huang; Zhi-Xin Chen |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't Date: 2007-05-24 |
Journal Detail:
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Title: Digestive diseases and sciences Volume: 53 ISSN: 0163-2116 ISO Abbreviation: Dig. Dis. Sci. Publication Date: 2008 Jan |
Date Detail:
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Created Date: 2007-12-17 Completed Date: 2008-02-19 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 7902782 Medline TA: Dig Dis Sci Country: United States |
Other Details:
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Languages: eng Pagination: 181-7 Citation Subset: AIM; IM |
Affiliation:
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Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, PR China. drchenfl@163.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
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pharmacology Apoptosis / drug effects, physiology* Arachidonate 12-Lipoxygenase / antagonists & inhibitors, biosynthesis* Blotting, Western Cell Proliferation / drug effects DNA Topoisomerases, Type II Electrophoresis, Agar Gel Enzyme Inhibitors / pharmacology Flavanones / pharmacology Humans Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors, biosynthesis* Phosphorylation Signal Transduction / physiology* Stomach Neoplasms / drug therapy, enzymology*, pathology Tumor Cells, Cultured Tumor Markers, Biological |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 0/Flavanones; 0/Tumor Markers, Biological; 491-67-8/baicalein; 59985-28-3/12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; EC 1.13.11.31/Arachidonate 12-Lipoxygenase; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3; EC 5.99.1.3/DNA Topoisomerases, Type II |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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