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。已经鉴定了三种同种型，最近的证据表明，PPARgamma和PPARa的药理学活化以及PPARgamma的抑制可以预防癌症。PPARgamma作为配体的靶点已被广泛研究，其强烈调节结直肠癌的发生。PPARgamma配体包括J系列的洋地黄素、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。虽然许多报道记载了PPARgamma配体在结肠直肠癌中的抗肿瘤活性，但除了PPARgamma激活之外，对这些作用负责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PPARgamma配体的抗肿瘤活性中起关键作用。本研究的目的是了解PPARgamma配体如何通过不同的机制调节NAG-1的表达并影响结直肠癌的发生。这项研究还可能为化学和环境因素如何影响癌症发展提供新的见解，并随后发展出一系列新的抗肿瘤化合物。具体的目的是：检查NAG-1表达的贡献，在PPARgamma配体诱导的细胞凋亡。表征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非依赖性方式诱导的基因谱。四.研究新型PPARy配体MCC-555的体内抗肿瘤作用及其在结直肠癌发生的不同阶段对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.