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 i s 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA111469-02
Application #
7035938
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Perloff, Marjorie
Project Start
2005-04-01
Project End
2010-02-28
Budget Start
2006-04-01
Budget End
2007-02-28
Support Year
2
Fiscal Year
2006
Total Cost
$244,124
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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