The Protective Effects of Conjugated Linoleic Acid Against Carcinogenesis

by Kemp, Michael Quentin.

The long-range goal of this project is to investigate the protective effects of conjugated linoleic acid (CLA) against carcinogenesis. In this dissertation, we demonstrate the mechanisms of CLA action on cell cycle progression and repression of polycyclic aromatic hydrocarbon (PAH)-induced Cyclooxygenase-2 (COX-2) in breast and colon cancer cells. CLA reduced the expression of factors required for G1 to S-phase transition including cyclins D1 and E, and hyperphoshorylated retinoblastoma Rb protein. In contrast, the over-expression of mutant p53 (175Arg to His) in MCF-7 cells prevented the CLA-dependent accumulation of p21 and the reduction of cyclin E levels suggesting that the expression of wild- type p53 is required for CLA-mediated activation of the G1 restriction point. We also report, CLA reduced the expression of COX-2 promoter activity induced by the aromatic hydrocarbon receptor (AhR)-ligand benzo[a]pyrene (B[a]P). Mutagenesis or deletion of potential xenobiotic responsive elements (XREs) within the COX-2 promoter abrogated its ability to be induced by the high affinity AhRligand