COX-2 Inhibitors, APC and Colon Cancer Prevention

描述(申请人提供)：APC肿瘤抑制基因突变导致FAP，并在大约80%的散发性结直肠癌中检测到。功能APC的缺失会导致TCF/β-catenin介导的转录激活。该通路的激活改变了许多基因的表达，如COX-2，这些基因与结直肠癌的发病机制有关。临床前和临床研究已经强调了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。该应用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(S)。我们已经证明，β-连环蛋白信号的激活通过诱导COX-2和mPGES-1来刺激前列腺素的生物合成。值得注意的是，解除调控的TCF/Beta-catenin信号刺激了这两个基因的转录，稳定了COX-2mRNA，同时阻止了它的翻译。EGFR/RAS信号的激活是结直肠肿瘤的常见事件，缓解了这一翻译障碍。在一个目标中，我们将定义这些效应背后的机制。第二个目标将是表征COX-2衍生产物在下游通路上的作用，这些下游通路已被认为与癌症发生有关。这一目标得到了PGE2和TXA2激活TCF/Beta-catenin介导的转录和EGFR信号的初步证据的支持，这表明这些信号通路之间存在相互作用。此外，PGE2和TXA2改变了TCF/Beta-catenin靶基因的转录后控制，这表明二十烷类化合物通过多种机制影响细胞生长。最后，我们已经证明，塞来昔布通过COX-2非依赖的机制“正常化”解除调控的TCF/β-连环蛋白介导的转录。因此，第三个目标将是进行更多的体外和体内研究，以进一步评估这些效果。这些研究将增强我们对COX-2和结直肠癌之间的机制联系的理解，并有可能帮助我们优化选择性COX-2抑制剂的治疗。

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.