COX-2 Inhibitors, APC and Colon Cancer Prevention

Summary

Principal Investigator: Kotha Subbaramaiah
Abstract: 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.
Funding Period: 2005-04-01 - 2010-02-28
more information: NIH RePORT

Top Publications

  1. pmc Selective visualization of cyclooxygenase-2 in inflammation and cancer by targeted fluorescent imaging agents
    Md Jashim Uddin
    AB Hancock, Jr Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Cancer Res 70:3618-27. 2010
  2. ncbi Histone deacetylase inhibitors suppress the induction of c-Jun and its target genes including COX-2
    Kentaro Yamaguchi
    Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA
    J Biol Chem 280:32569-77. 2005
  3. ncbi Levels of NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase are reduced in inflammatory bowel disease: evidence for involvement of TNF-alpha
    Taisuke Otani
    Department of Medicine, Weill Medical College of Cornell University, New York, New York, USA
    Am J Physiol Gastrointest Liver Physiol 290:G361-8. 2006
  4. ncbi Desmethyl derivatives of indomethacin and sulindac as probes for cyclooxygenase-dependent biology
    Andrew S Felts
    ACS Chem Biol 2:479-83. 2007
  5. pmc Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors
    Masayuki Fukata
    Inflammatory Bowel Disease Center, Mount Sinai School of Medicine, New York, New York, USA
    Gastroenterology 133:1869-81. 2007
  6. pmc Sulindac derivatives that activate the peroxisome proliferator-activated receptor gamma but lack cyclooxygenase inhibition
    Andrew S Felts
    Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Med Chem 51:4911-9. 2008
  7. pmc Bile acids inhibit NAD+-dependent 15-hydroxyprostaglandin dehydrogenase transcription in colonocytes
    Akira Miyaki
    Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA
    Am J Physiol Gastrointest Liver Physiol 297:G559-66. 2009

Detail Information

Publications7

  1. pmc Selective visualization of cyclooxygenase-2 in inflammation and cancer by targeted fluorescent imaging agents
    Md Jashim Uddin
    AB Hancock, Jr Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Cancer Res 70:3618-27. 2010
    ....
  2. ncbi Histone deacetylase inhibitors suppress the induction of c-Jun and its target genes including COX-2
    Kentaro Yamaguchi
    Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA
    J Biol Chem 280:32569-77. 2005
    ..This led, in turn, to reduced expression of several activator protein-1-dependent genes (COX-2, cyclin D1, collagenase-1). These findings provide new insights into the mechanisms underlying the antitumor activity of HDAC inhibitors...
  3. ncbi Levels of NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase are reduced in inflammatory bowel disease: evidence for involvement of TNF-alpha
    Taisuke Otani
    Department of Medicine, Weill Medical College of Cornell University, New York, New York, USA
    Am J Physiol Gastrointest Liver Physiol 290:G361-8. 2006
    ..The decrease in amounts of 15-PGDH in inflamed mucosa can be explained at least, in part, by TNF-alpha-mediated suppression of 15-PGDH transcription...
  4. ncbi Desmethyl derivatives of indomethacin and sulindac as probes for cyclooxygenase-dependent biology
    Andrew S Felts
    ACS Chem Biol 2:479-83. 2007
    ..These compounds serve as useful probes of COX-dependent biology and may represent leads for antidiabetic and anticancer drugs...
  5. pmc Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors
    Masayuki Fukata
    Inflammatory Bowel Disease Center, Mount Sinai School of Medicine, New York, New York, USA
    Gastroenterology 133:1869-81. 2007
    ..The molecular mechanisms linking inflammation and colon carcinogenesis are incompletely understood. We tested the hypothesis that Toll-like receptor 4 (TLR4) is involved in tumorigenesis in the setting of chronic inflammation...
  6. pmc Sulindac derivatives that activate the peroxisome proliferator-activated receptor gamma but lack cyclooxygenase inhibition
    Andrew S Felts
    Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Med Chem 51:4911-9. 2008
    ..Taken together, these compounds represent potential leads in the development of novel PPARgamma agonists...
  7. pmc Bile acids inhibit NAD+-dependent 15-hydroxyprostaglandin dehydrogenase transcription in colonocytes
    Akira Miyaki
    Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA
    Am J Physiol Gastrointest Liver Physiol 297:G559-66. 2009
    ..These results provide new mechanistic insights into the link between bile acids and gastrointestinal carcinogenesis...