PPAR-gamma ligands in colorectal cancer

结直肠癌中的 PPAR-γ 配体

• 批准号: 7148914
• 负责人: SEUNG Joon BAEK
• 金额: $ 20.59万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7148914
• 关键词: colorectal neoplasms; genes; ligands; neoplasm /cancer

DESCRIPTION (provided by applicant): The peroxisome proliferator activated receptors (PPARs) are ligand-activated nuclear hormone receptors and a potential target for the prevention and treatment of several cancers. Three isoforms have been dentified and recent evidence suggests that pharmacological activation of PPARgamma and PPARa, and inhibition of PPARgamma, may prevent cancer. PPARgamma has been extensively investigated as a target for ligands, which strongly modulate colorectal carcinogenesis. PPARgamma ligands include prostaglandins of the J series, the synthetic antidiabetic thiazolidinediones, and oxidative metabolites of polyunsaturated fatty acids. While numerous reports document the anti-tumorigenic activity of PPARgamma ligands in colorectal cancer the molecular mechanisms responsible for these effects are not known beyond PPARgamma activation. We have preliminary evidence that PPARgamma ligands induce expression of the pro-apoptotic gene NAG-1 (nonsteroidal anti-inflammatory drug activated gene) in a PPARgamma- dependent and independent manner, and hypothesize that this induction of NAG-1 plays a pivotal role in the anti-tumorigenic activity of PPARgamma ligands. The research objectives of this proposal are to understand how PPARgamma ligands regulate NAG-1 expression by different mechanisms and affect the development of colorectal cancer. This study may also provide new insights into how chemical and environmental factors influence cancer development with subsequent evolution of a new family of novel anti-tumorigenic compounds. The specific aims are; To examine the contribution of NAG-1 expression in PPARgamma ligand-induced apoptosis. To characterize cis- and trans-acting elements responsible for the induction of NAG-1 expression by PPARgamma ligands. . To examine the profile of genes which are induced by PPARgamma ligands in a PPARgamma- independent manner. IV. To investigate the in vivo anti-tumorigenic effects of a novel PPARy ligand, MCC-555, and its affects on NAG-1 expression at different stages of colorectal carcinogenesis.

描述(申请人提供)：过氧化物酶体增殖物激活受体(PPAR)是配体激活的核激素受体，是预防和治疗几种癌症的潜在靶点。目前已鉴定出三种亚型，最近的证据表明，PPARGamma和PPARa的药理激活，以及PPARGamma的抑制，可能会预防癌症。PPARGamma已被广泛研究为配体的靶点，这些配体强烈调控结直肠癌的发生。PPARGamma配体包括J系列的前列腺素、合成的抗糖尿病的噻唑烷二酮和多不饱和脂肪酸的氧化代谢物。虽然许多报告证明了PPARGamma配体在结直肠癌中的抗肿瘤活性，但除了PPARGamma激活外，这些作用的分子机制尚不清楚。我们已有初步证据表明，PPARGamma配体以依赖和独立的方式诱导促凋亡基因NAG-1(非甾体抗炎药激活基因)的表达，并假设这种NAG-1的诱导在PPARGamma配体的抗肿瘤活性中起关键作用。本研究的目的是了解PPARγ配体如何通过不同的机制调节NAG-1的表达，从而影响结直肠癌的发生发展。这项研究还可能为化学和环境因素如何影响癌症的发展以及随后新的抗肿瘤化合物家族的进化提供新的见解。其具体目的是：检测NAG-1表达在PPAR-γ配体诱导的细胞凋亡中的作用。鉴定PPARγ配体诱导NAG-1表达的顺式和反式作用元件。。以不依赖于PPAR的方式检测由PPAR-γ配体诱导的基因图谱。IV.研究新型PPARy配体MCC-555的体内抗肿瘤作用及其对结直肠癌不同阶段NAG-1表达的影响。