PPAR-gamma ligands in colorectal cancer

描述（由申请人提供）：过氧化物酶体增殖物激活受体（PPARs）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点。已经确定了三种亚型，最近的证据表明，PPARgamma和PPARgamma的药理激活以及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系列的前列腺素、合成的抗糖尿病噻唑烷二酮和多不饱和脂肪酸的氧化代谢物。虽然许多报告记录了PPARgamma配体在结直肠癌中的抗肿瘤活性，但除PPARgamma激活外，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，并假设这种诱导NAG-1在PPARgamma配体的抗肿瘤活性中起关键作用。本课题的研究目的是了解PPARgamma配体如何通过不同机制调节NAG-1的表达，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提供新的见解，并随后进化出新的抗肿瘤化合物家族。具体目标是；探讨NAG-1表达在PPARgamma配体诱导的细胞凋亡中的作用。表征PPARgamma配体诱导NAG-1表达的顺式和反式元件。目的：研究PPARgamma配体以不依赖于PPARgamma的方式诱导的基因谱。四、探讨新型pparty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。

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.