PPAR-gamma ligands in colorectal cancer

结直肠癌中的 PPAR-γ 配体

• 批准号: 7434029
• 负责人: SEUNG Joon BAEK
• 金额: $ 19.99万
• 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/7434029
• 关键词: 2,4-thiazolidinedione; Affect; Antidiabetic Drugs; Apoptosis; Apoptotic; Binding; Chemicals; Colorectal; Colorectal Cancer; Complex; Development; Environmental Risk Factor; Evolution; Family; Figs - dietary; GDF15 gene; Gene Mutation; Genes; Inflammatory Response; Ligands; Malignant Neoplasms; Metabolic Diseases; Molecular; Non-Steroidal Anti-Inflammatory Agents; Nuclear Hormone Receptors; PPAR gamma; Peroxisome Proliferator-Activated Receptors; Play; Polyunsaturated Fatty Acids; Prevention; Prostaglandins; Protein Isoforms; RXR; Regulator Genes; Report (document); Research; Response Elements; Role; Series; Staging; Thiazolidinediones; carcinogenesis; in vivo; insight; lipid metabolism; novel; prevent; tumorigenic

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（由申请人提供）：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，是预防和治疗多种癌症的潜在靶标。已鉴定出三种亚型，最近的证据表明 PPARgamma 和 PPARa 的药理学激活以及 PPARgamma 的抑制可能预防癌症。 PPARgamma 作为配体的靶标已被广泛研究，该配体强烈调节结直肠癌的发生。 PPARgamma 配体包括 J 系列前列腺素、合成抗糖尿病药物噻唑烷二酮和多不饱和脂肪酸的氧化代谢产物。虽然大量报告记录了 PPARgamma 配体在结直肠癌中的抗肿瘤活性，但除了 PPARgamma 激活之外，导致这些作用的分子机制尚不清楚。我们有初步证据表明 PPARgamma 配体以 PPARgamma 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 NAG-1 的这种诱导在细胞凋亡中发挥着关键作用。 PPARγ配体的抗肿瘤活性。本提案的研究目的是了解PPARγ配体如何通过不同机制调节NAG-1表达并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发展以及随后新型抗肿瘤化合物新家族的进化提供新的见解。具体目标是；检测 NAG-1 表达在 PPARgamma 配体诱导的细胞凋亡中的作用。表征负责 PPARgamma 配体诱导 NAG-1 表达的顺式和反式作用元件。 。检测由 PPARgamma 配体以 PPARgamma 独立方式诱导的基因谱。四．目的 研究新型 PPARγ 配体 MCC-555 的体内抗肿瘤作用，及其在结直肠癌发生不同阶段对 NAG-1 表达的影响。