Background: The United States is one of the countries with the highest incidence of colon cancer. Toxic bile acids, such as the lithocholic acid (LCA), are known to promote colon cancer and contribute to the colon cancer-causing effects of a high-fat diet. LCA promotes colon cancer by increasing cell proliferation and suppressing apoptosis especially in the presence of chemical cancer initiators. The detoxification of bile acids is facilitated by the phase I cytochrome P450 (CYP) enzymes, the phase II sulfotransferases (SULT), and the drug effluxing transporters. The expression of these gene products is controlled by PXR, an orphan nuclear receptor functioning as a species-specific xenobiotic receptor. Objective/hypothesis: The long-term goals of this study are to determine the molecular mechanisms by which PXR regulates bile acid detoxification and the implication of this regulation in colon cancer prevention. We hypothesize that bile acid detoxifying enzymes and transporters are transcriptional targets of PXR. Activation of PXR by chemical or genetic means promotes bile acid detoxification, thus preventing colon cancer.
Specific aims and study design: (1) To determine whether activation of PXR is sufficient to inhibit bile acid-promoted colon cancer cell growth. Colon cancer cells overexpressing hPXR will be generated and the effect of PXR activation on LCA catabolism and LCA-promoted cell proliferation will be examined; (2) To determine whether PXR activation is necessary and sufficient to reduce bile acid-promoted colonic carcinogenesis. Dimethylhydrazine (DMH)-initiated and LCA-promoted colonic carcinogenesis will be performed in mice bearing """"""""humanized"""""""", heightened, or compromised PXR activities; (3) To determine whether genetic activation of PXR is sufficient to inhibit dietary fat-promoted colonic carcinogenesis. DMH-initiated and dietary fact-promoted colonic carcinogenesis will be performed in mice expressing constitutively activated hPXR; and (4) To determine the molecular basis by which PXR regulates the expression of bile acid detoxifying enzymes and transporters. The activation of the detoxifying enzyme and transporter gene promoters by PXR will be examined by transfection and reporter gene assays. Cancer relevance: These studies will contribute to understand the molecular mechanisms by which PXR controls bile acid detoxification and how these regulatory mechanisms can be applied in preventing colon cancer. It is anticipated that the development of selective PXR agonists may represent a novel strategy to eliminate toxic bile acids and to prevent colon cancer.
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