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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA108975-05
Application #
7841855
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Arya, Suresh
Project Start
2006-07-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
5
Fiscal Year
2010
Total Cost
$199,929
Indirect Cost
Name
University of Tennessee Knoxville
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
003387891
City
Knoxville
State
TN
Country
United States
Zip Code
37996
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