| 常 剑,陶 京,朱忠超,方 琦,李汉军,朱孔凡.花生四烯酸通过COX-2酶代谢氧化失活PTEN促进结直肠癌生长[J].,2020,(21):4001-4006 |
| 花生四烯酸通过COX-2酶代谢氧化失活PTEN促进结直肠癌生长 |
| Arachidonic Acid Promotes the Growth of Colorectal Cancer by Oxidative Inactivation of PTEN Through COX-2 Enzyme Metabolism |
| 投稿时间：2020-05-28 修订日期：2020-06-24 |
| DOI：10.13241/j.cnki.pmb.2020.21.001 |
| 中文关键词: 结直肠癌 COX-2 PTEN/PI3K/AKT途径 花生四烯酸 |
| 英文关键词: Colorectal cancer COX-2 PTEN/PI3K/AKT pathway Arachidonic acid |
| 基金项目:国家自然科学基金项目（81702368）；湖北省自然科学基金项目（2016CFB121） |
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| 中文摘要: |
| 摘要 目的：本研究旨在阐明过表达COX-2的结直肠癌中花生四烯酸代谢与PTEN及其下游通路的相互关系。方法：利用过表达COX-2结直肠癌细胞系CT26和Apc Min/+小鼠腺瘤模型，联合花生四烯酸、COX-2抑制剂NS-398和COX-2基因敲除的干预，采用流式细胞仪检测细胞凋亡、细胞周期及活性氧的产生；Transwell和克隆形成试验观察细胞的迁移和增殖能力；Western blot和免疫组化检测PTEN及其下游相关蛋白的表达。结果：花生四烯酸通过COX-2酶代谢产生活性氧并失活PTEN抑癌基因表达，从而激活PI3K-AKT蛋白促进CT26结直肠癌细胞迁移和增殖，抑制细胞凋亡；而COX-2抑制剂NS-398阻止了花生四烯酸在CT26结直肠癌细胞中的恶性生物学行为。同时，在COX-2基因敲除Apc Min/+小鼠腺瘤组织中，减弱了氧化应激水平，增加了PTEN表达，抑制了PI3K-AKT磷酸化，进一步抑制腺瘤生长，提高小鼠生存率。结论：花生四烯酸通过COX-2酶代谢产生活性氧下调PTEN活性，并激活PI3K-AKT促进结直肠癌生长；COX-2抑制剂可间接促进PTEN表达，抑制结直肠癌生长，能够作为CRC的潜在治疗靶点。 |
| 英文摘要: |
| ABSTRACT Objective: This study aimed to clarify the relationship between arachidonic acid metabolism, PTEN and its downstream pathways in COX-2 overexpressing colorectal cancer. Methods: By using an over-expressed COX-2 of colorectal cancer cell line CT26 and Apc Min/+ mouse adenoma model, combined with arachidonic acid, COX-2 inhibitor NS-398 treatment and COX-2 gene knockout intervention, flow cytometry was used to detect apoptosis, cell cycle and the generation of reactive oxygen species; transwell and colony formation assay were used to test the migration and proliferation capacity of cells; western blot and immunohistochemistry were used to detect the expression of PTEN and its downstream related proteins. Results: In CT26 colorectal cancer， arachidonic acid is metabolized by COX-2 enzymes to produce reactive oxygen species and inactivate PTEN, thereby activating PI3K-AKT protein to promote cell migration and proliferation, and inhibit apoptosis; while COX-2 inhibitor NS-398 prevents the malignant biological behavior of arachidonic acid in CT26 colorectal cancer cells. Moreover, in the COX-2 gene knockout Apc Min/+ mouse adenomas tissue , NS-398 treatment reduced the level of oxidative stress, increased the expression of PTEN, inhibited the phosphorylation of PI3K-AKT, further inhibited the growth of adenomas, and improved the survival rate of mice. Conclusion: Arachidonic acid could produce active oxygen to down-regulate PTEN activity and activate PI3K-AKT to promote colorectal cancer growth through COX-2 enzyme; COX-2 inhibitors can indirectly promote PTEN expression and inhibit colorectal cancer growth, and can act as a potential target for CRC treatment. |
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