Role Of Lipids In Colon, Prostate, And Other Cancers

脂质在结肠癌、前列腺癌和其他癌症中的作用

• 批准号: 7007409
• 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/7007409
• 关键词: angiogenesis; apoptosis; arachidonate; biological signal transduction; carcinogenesis; cell growth regulation; cell proliferation; colon neoplasms; gene expression; genetic regulation; human tissue; laboratory mouse; linoleate; lipid metabolism; lipoxygenase; molecular oncology; neoplasm /cancer genetics; prostaglandin endoperoxide synthase; prostaglandins; prostate neoplasms; protein localization; protein structure function; tissue /cell culture; vascular endothelial growth factors

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.

花生四烯酸(AA)和亚油酸(LA)代谢的重要性得到了动物和人类流行病学研究的支持，这些研究表明，阿司匹林和其他抑制COX活性的非甾体抗炎药可以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，非类固醇抗炎药可以减少致癌物诱导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生和发展中起着重要作用，但其机制尚不清楚。COX和LOX的表达以及NSAID治疗与细胞凋亡、细胞生长、细胞分化和血管生成的改变有关。我们正在检测花生四烯酸和亚油酸的代谢，以及人类细胞系中COX-1和COX-2以及脂氧合酶的表达。除COX-2外，15-脂氧合酶在结直肠癌和前列腺癌中的表达也较高。数据支持组蛋白乙酰化调节人肠上皮细胞15-脂氧合酶-1表达的假说。在前列腺细胞中，15-LOX-1具有促肿瘤作用，而在结直肠组织中，脂氧合酶具有抗肿瘤作用。这些脂氧合酶及其代谢产物改变了生长因子信号通路，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，该实验室正在研究COX-1和COX-2在细胞中的表达和调控。一个意想不到的发现是，HDAC抑制剂上调了脑细胞中COX-1的表达，而不是15-LOX-1。我们的计划是继续研究15-LOX和COX-1&2的调控，并重点研究这些酶如何促进癌症的发展。