Role Of Lipids In Colon, Breast, And Other Cancers

脂质在结肠癌、乳腺癌和其他癌症中的作用

• 批准号: 6838371
• 负责人: Thomas 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/6838371
• 关键词: apoptosis; arachidonate; butyrates; carcinogenesis; cell line; cell proliferation; colon neoplasms; enzyme activity; enzyme inhibitors; human tissue; laboratory mouse; linoleate; lipid metabolism; lipoxygenase; neoplasm /cancer pharmacology; nonsteroidal antiinflammatory agent; phospholipase A2; prostaglandin endoperoxide synthase; prostaglandins; tissue /cell culture

The importance of arachidonic acid (AA) and linoleic acid (LA) metabolism is supported by animal and human epidemiology studies that indicate that aspirin and other NSAIDs that inhibit Cox activity, reduce the incidence and mortality of colon cancer and reduce 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. Prostaglandins and other lipids play a major role in the development and progression of colon and other cancers but the mechanism is not clear. The expression of Cox and LOX and NSAID treatment is linked to altered apoptosis, cell growth, cell differentiation and angiogenesis. We are examining arachidonic acid and linoleic acid metabolism, and the expression of Cox-1 and -2, and lipoxygenases in human cell lines. In addition to Cox-2, the expression of 15-lipoxygenase is higher in colorectal and prostate tumors. Data support the hypothesis that histone acetylation regulates the expression of 15-lipoxygenase-1 in human intestinal epithelial cells. In prostate cells 15-LOX-1 has a pro-tumorigenic effect while in colorectal tissue the lipoxygenase has an anti-tumorigenic effect. These lipoxygenases and their metabolites alter growth factor signaling pathways and 15-HETE and 13-HODE, the metabolites of AA and LA have opposing biological responses. In addition, the laboratory is studying the expression and regulation of Cox-1 and Cox-2 in cells. One unexpected finding is the up-regulation of Cox-1 but not 15-LOX-1 by HDAC inhibitors in brain cells. Our plans are to continue to investigate the regulation of 15-LOX and Cox-1 &-2 and to focus on how these enzyme contribute to the development of cancers.

动物和人类流行病学研究支持花生四烯酸（AA）和亚油酸（LA）代谢的重要性，这些研究表明阿司匹林和其他NSAID可抑制考克斯活性，降低结肠癌的发病率和死亡率，并减少家族性息肉病患者的息肉。对啮齿动物的实验研究表明，非甾体类抗炎药可减少致癌物诱发的结肠肿瘤的大小和数量。前列腺素和其他脂质在结肠癌和其他癌症的发展和进展中起着重要作用，但其机制尚不清楚。考克斯和LOX的表达和NSAID治疗与改变的细胞凋亡、细胞生长、细胞分化和血管生成有关。我们正在研究花生四烯酸和亚油酸的代谢，以及考克斯-1和-2，和脂氧合酶在人类细胞系中的表达。除考克斯-2外，15-脂氧合酶在结直肠和前列腺肿瘤中的表达更高。数据支持的假设，组蛋白乙酰化调节15-脂氧合酶-1在人类肠上皮细胞的表达。在前列腺细胞中，15-LOX-1具有促肿瘤发生作用，而在结肠直肠组织中，脂氧合酶具有抗肿瘤发生作用。这些脂氧合酶及其代谢产物改变生长因子信号通路，AA和LA的代谢产物15-HETE和13-HODE具有相反的生物学反应。此外，实验室正在研究考克斯-1和考克斯-2在细胞中的表达和调控。一个意想不到的发现是脑细胞中HDAC抑制剂上调考克斯-1而非15-LOX-1。我们的计划是继续研究15-LOX和考克斯-1和-2的调节，并关注这些酶如何促进癌症的发展。