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12-Lipoxygenase Induces Apoptosis of Human Gastric Cancer AGS Cells via the ERK1/2 Signal Pathway

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Abstract

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 μmol 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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Acknowledgments

This work was supported by National Natural Science Foundation of China (Grant30300154) and Education Foundation of Fujian Province (Grant JA03094).

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Authors and Affiliations

  1. Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, P.R. China

    Feng-Lin Chen & Jie-Ping Yu

  2. Department of Gastroenterology, Union Hospital of Fujian Medical University, Fuzhou, 350001, Fujian Province, P.R. China

    Xiao-Zhong Wang, Jian-Ying Li, Cai-Yun Huang & Zhi-Xin Chen

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  1. Feng-Lin Chen
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  2. Xiao-Zhong Wang
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Correspondence to Feng-Lin Chen or Xiao-Zhong Wang.

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Chen, FL., Wang, XZ., Li, JY. et al. 12-Lipoxygenase Induces Apoptosis of Human Gastric Cancer AGS Cells via the ERK1/2 Signal Pathway. Dig Dis Sci 53, 181–187 (2008). https://doi.org/10.1007/s10620-007-9841-1

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  • DOI: https://doi.org/10.1007/s10620-007-9841-1

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