ROLE OF LIPIDS IN COLON CANCER

脂质在结肠癌中的作用

• 批准号: 6162251
• 负责人: T ELING
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6162251
• 关键词: arachidonate; butyrates; carcinogenesis; colon neoplasms; enzyme activity; enzyme inhibitors; linoleate; lipid metabolism; lipoxygenase; neoplasm /cancer pharmacology; nonsteroidal antiinflammatory agent; phospholipase A2; prostaglandin endoperoxide synthase; tissue /cell culture

Summary of Work: The importance of arachidonic acid and linoleic acid metabolism is supported by animal and human epidemiology studies that indicate that aspirin and other NSAIDs reduce the incidence and mortality of colon cancer. These drugs also induce regression of rectal polyps in patients with familial polyposis. Experimental studies with rodents indicate that NSAIDs reduce both the size and number of colon tumors induced by carcinogens. Recent studies reported that PGHS-2 is significantly expressed in colon tumors compared to neighboring normal tissue and that mutation in the APC gene is directly linked to the expression of PGHS-2 in the tumors. Thus, prostaglandins play a major role in the development and progression of colon cancer but the mechanism is not clear. Some data suggest effects of prostaglandins are via modulation of apoptosis. We are examining arachidonic and linoleic acid metabolism,and the expression of PGHS-1 and -2, lipoxygenases, and cPLA2 in human cell lines. We observed, in SW-480 and other human colon cells that butyrate-induced differentiation results in an increased expression of PGHS-1 and a lipoxygenase. PGHS-2 expression is high in these cancer cells but expression is not altered by butyrate treatement. Butyrate also induces apoptosis but the addition of PGHS inhibitors did not alter the apoptosis in these cells. We are also using rat intestinal cell lines that highly express PGHS-2 and are used as a model of colon cancer. These studies will further define the potential use of NSAID as chemotherapeutic agents and hopefully better define the role of lipids in colon cancer.

工作总结：花生四烯酸和亚油酸的重要性 新陈代谢得到动物和人类流行病学研究的支持 表明阿司匹林和其他非甾体抗炎药可降低发病率和死亡率 结肠癌。这些药物还可诱导直肠息肉消退 家族性息肉病患者。 啮齿动物实验研究 表明非甾体抗炎药可以减少结肠肿瘤的大小和数量 由致癌物质诱发。 最近的研究表明 PGHS-2 与邻近正常组织相比，在结肠肿瘤中显着表达 组织中的 APC 基因突变与 PGHS-2在肿瘤中的表达。因此，前列腺素起着重要作用 结肠癌发生、发展过程中的作用，但其机制 尚不清楚。一些数据表明前列腺素的作用是通过 细胞凋亡的调节。 我们正在检查花生四烯酸和亚油酸 代谢以及 PGHS-1 和 -2、脂氧合酶和 cPLA2 的表达 在人类细胞系中。 我们在 SW-480 和其他人类结肠细胞中观察到 丁酸盐诱导的分化导致表达增加 PGHS-1 和脂氧合酶。 PGHS-2 在这些癌症中表达较高 细胞，但丁酸盐处理不会改变表达。 丁酸盐 也诱导细胞凋亡，但添加 PGHS 抑制剂并没有改变 这些细胞的凋亡。 我们还使用大鼠肠细胞 高度表达 PGHS-2 的细胞系被用作结肠癌模型。 这些研究将进一步确定 NSAID 的潜在用途： 化疗药物并有望更好地定义脂质在 结肠癌。