COX-2 Inhibitors, APC and Colon Cancer Prevention

COX-2 抑制剂、APC 和结肠癌预防

• 批准号: 7568910
• 负责人: KOTHA SUBBARAMAIAH
• 金额: $ 23.7万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7568910
• 关键词: Adenomatous Polyposis Coli; Affect; Anabolism; CCND1 gene; Cell Nucleus; Cessation of life; Clinical Data; Clinical Research; Clinical Trials; Colon Carcinoma; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Colorectal Polyp; Coxibs; Data; Developed Countries; Dinoprostone; Disease; EGF gene; Eicosanoids; Engineering; Epidemiologic Studies; Epidemiology; Epidermal Growth Factor Receptor; Event; Failure; Feedback; Gene Targeting; Genes; Genetic Transcription; Growth Factor; Health; High Prevalence; In Vitro; Incidence; Intestinal Neoplasms; Knowledge; Laboratory Study; Link; Mediating; Messenger RNA; Molecular Target; Mus; Mutation; PTEN gene; Pathogenesis; Pathway interactions; Patients; Play; Post-Transcriptional Regulation; Prevention; Prostaglandin H2; Prostaglandins; Risk; Rofecoxib; Role; Signal Induction; Signal Transduction; Time; Translations; Tumor Suppressor Genes; bcl-1 Genes; beta catenin; c-myc Genes; cancer prevention; carcinogenesis; celecoxib; cell growth; clinically relevant; cyclooxygenase 2; functional loss; in vivo; mortality; mouse PGE synthase 1; mutant; overexpression; polyposis; pre-clinical; prevent; prostaglandin E synthase; research study; success; therapeutic target; tumor progression

DESCRIPTION (provided by applicant): Mutations in the APC tumor suppressor gene cause FAP and are detected in approximately 80% of sporadic colorectal cancers. A loss of functional APC results in activation of TCF/Beta-catenin-mediated transcription. Activation of this pathway alters the expression of numerous genes, e.g., COX-2, that have been implicated in the pathogenesis of colorectal cancer. Preclinical and clinical studies have highlighted the potential importance of COX-2 as a therapeutic target for preventing and possibly treating colorectal cancer. The long-term objective of this application is to better understand the mechanistic link between APC, COX-2 and colorectal carcinogenesis as well as the mechanism(s) of action of selective COX-2 inhibitors. We have shown that activation of Beta-catenin signaling stimulates prostanoid biosynthesis by inducing COX-2 and mPGES-1. Notably, deregulated TCF/Beta-catenin signaling stimulated the transcription of both genes, stabilized COX-2 mRNA while blocking its translation. Activation of EGFR/Ras signaling, a common event in colorectal neoplasia, relieved this translational block. In one aim, we will define the mechanisms underlying these effects. A second aim will be to characterize the effects of COX-2-derived products on downstream pathways that have been implicated in carcinogenesis. This aim is supported by preliminary evidence that PGE2 and TXA2 activate TCF/Beta-catenin-mediated transcription and EGFR signaling suggesting cross-talk between these pathways. Additionally, PGE2 and TXA2 altered the post-transcriptional control of TCF/Beta-catenin target genes suggesting that eicosanoids affect cell growth by multiple mechanisms. Finally, we have shown that celecoxib "normalizes" deregulated TCF/Beta-catenin-mediated transcription by a COX-2- independent mechanism. Hence, a third aim will be to perform additional in vitro and in vivo studies to further evaluate these effects. These studies will enhance our understanding of the mechanistic link between COX-2 and colorectal cancer and potentially assist us in optimizing the use of selective COX-2 inhibitors as therapy.

描述（由申请人提供）：APC 肿瘤抑制基因的突变会导致 FAP，并在大约 80% 的散发性结直肠癌中检测到。功能性 APC 的丧失会导致 TCF/β-连环蛋白介导的转录激活。该通路的激活会改变许多基因的表达，例如 COX-2，这些基因与结直肠癌的发病机制有关。临床前和临床研究强调了 COX-2 作为预防和可能治疗结直肠癌的治疗靶点的潜在重要性。本申请的长期目标是更好地了解 APC、COX-2 与结直肠癌发生之间的机制联系以及选择性 COX-2 抑制剂的作用机制。我们已经证明，β-连环蛋白信号传导的激活通过诱导 COX-2 和 mPGES-1 来刺激前列腺素生物合成。值得注意的是，失调的 TCF/β-连环蛋白信号传导刺激了这两个基因的转录，稳定了 COX-2 mRNA，同时阻断了其翻译。 EGFR/Ras 信号传导的激活（结直肠肿瘤中的常见事件）缓解了这种翻译障碍。我们的一个目标是定义这些影响背后的机制。第二个目标是表征 COX-2 衍生产物对与致癌有关的下游途径的影响。这一目标得到了初步证据的支持，即 PGE2 和 TXA2 激活 TCF/β-连环蛋白介导的转录和 EGFR 信号传导，表明这些途径之间存在串扰。此外，PGE2 和 TXA2 改变了 TCF/β-catenin 靶基因的转录后控制，表明类二十烷酸通过多种机制影响细胞生长。最后，我们发现塞来昔布通过 COX-2 独立机制使 TCF/β-连环蛋白介导的转录失调“正常化”。因此，第三个目标是进行额外的体外和体内研究以进一步评估这些影响。这些研究将增强我们对 COX-2 与结直肠癌之间机制联系的理解，并可能帮助我们优化选择性 COX-2 抑制剂的治疗用途。

项目成果

Bile acids inhibit NAD+-dependent 15-hydroxyprostaglandin dehydrogenase transcription in colonocytes.

胆汁酸抑制结肠细胞中 NAD 依赖性 15-羟基前列腺素脱氢酶转录。

• DOI: 10.1152/ajpgi.00133.2009
• 发表时间: 2009
• 期刊: American journal of physiology. Gastrointestinal and liver physiology
• 作者: Miyaki,Akira;Yang,Peiying;Tai,Hsin-Hsiung;Subbaramaiah,Kotha;Dannenberg,AndrewJ
• 通讯作者: Dannenberg,AndrewJ