Ligand Activation of Peroxisome Proliferator-Activated Receptor Beta Induces Terminal Differentiation and Attenuates Colon Cancer
Open Access
- Author:
- Hollingshead, Holly Elizabeth
- Graduate Program:
- Biochemistry, Microbiology, and Molecular Biology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- May 07, 2007
- Committee Members:
- Jeffrey Maurice Peters, Committee Chair/Co-Chair
Gary H Perdew, Committee Member
Richard John Frisque, Committee Member
Ross Cameron Hardison, Committee Member
David John Vandenbergh, Committee Member - Keywords:
- PPAR
colon cancer
colon - Abstract:
- In the last decade, the physiological roles of the peroxisome proliferator-activated receptor beta (PPARbeta) have begun to emerge. It is now known as a key regulator of a battery of genes involved a number of metabolic processes. PPARbeta is highly expressed in epithelial tissues, and it has become clear that the receptor functions in the development of a number of epithelial cancers, including cancer of the colon. The specific role of PPARbeta in colon cancer is uncertain, however, due to current inconsistencies in the literature. While some evidence suggests that PPARbeta can potentiate colon cancer, a growing body of evidence suggests that PPARbeta can attenuate colon cancer. In the present studies, the role of PPARbeta in the development of colon carcinogenesis was examined. Using both genetic and chemical models, it was demonstrated that PPARbeta attenuates colon cancer. Supporting these results, it was shown that PPARbeta mRNA expression is decreased in colon adenomas, consistent with a number of previous reports and in contrast to others. Further studies using a PPARbeta-null mouse model and a highly specific PPARbeta ligand revealed that ligand activation inhibits the development of colon cancer in a dose-dependent manner, and this inhibition is due to induction of terminal differentiation in the colonocotyes, associated with the subsequent induction of apoptosis and inhibition of cell proliferation. On a molecular level, using quantitative realtime PCR and ChIP analyses, these studies showed that terminal differentiation induced by ligand activation of PPARbeta is a result of the direct transcriptional activation of a number of target genes including ADRP, FABP and cathepsin E, all markers of differentiation in the colon. Through experiments in cell culture using three distinct colon cancer cell lines, these studies demonstrated that ligand activation of PPARbeta inhibits cell proliferation, and this inhibition is seen independent of the presence or absence of serum/growth factors. Additional analyses in these cells determined that discrepancies in the literature are not a result of the structural differences between ligands, nor are they a result of the differences between in vivo and in vitro model systems. To begin to further characterize the molecular changes underlying this PPARbeta-dependent attenuation of colon cancer, experiments were done using a PPARbeta ligand coupled with a known inhibitor of colon cancer, the COX2-inhibitor nimesulide. These studies revealed that both ligand activation of PPARbeta and COX2 inhibition attenuate the development of colon cancer independently. However, these two pathways (PPARbeta activation and COX2 inhibition) may work additively or synergistically to elicit an enhanced attenuation of colon cancer. Finally, the studies performed here show that PPARbeta has an anti-inflammatory role in the colon, protecting from experimentally-induced colitis. This role, however, appears to be independent of ligand activation, and further research must be performed to delineate the mechanisms of this anti-inflammatory function. The ability of PPARbeta to be anti-inflammatory has strong implications in colon cancer, as it has been shown that attenuation of inflammation corelates well with attenuation of colon cancer. Collectively, the experiments performed in these studies provide strong evidence that PPARbeta attenuates colon carcinogenesis through induction of terminal differentiation in colonocytes, with the subsequent induction of apoptosis and inhibition of cell proliferation. These works will help to clarify the current controversies in the literature and provide strong evidence that ligands for PPARbeta could aid in the treatment and/or prevention of colon cancer.