Pregnane X Receptor as a Regulator of Multi-Drug Resistance in Prostate Cancer

Southern Illinois University Sch Of Med, Springfield IL

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Prostate cancer is one of most common cancers afflicting American men and chemotherapy is a frequently used treatment modality in the disease management. However, the efficacy of chemotherapy is limited by the drug resistance presented by tumor cells. The induction of drug metabolizing enzymes (DMEs) and efflux transporters has been regarded as one of the major mechanisms of drug resistance. As a master transcription factor of DMEs and efflux transporters, pregnane X receptor (PXR), an orphan nuclear receptor known for its activation by many clinical drugs, is hypothesized as a novel regulator of multi-drug resistance in cancers. The role of PXR in multi-drug resistance of PXR is underscored by its two capabilities. First, PXR can be activated by a variety of structurally diverse compounds including many clinically used drugs and herbal supplements. Second, PXR activation stimulates the expression of important DMEs and efflux transporters, which in turn impact on the efficacy of chemotherapy. There are few direct studies being performed on the role of PXR in the responses of prostate cancer cells toward chemotherapy or in the acquisition of multi-drug resistance of cancer cells. The long term objective is to elucidate the functions of PXR in drug resistance of tumor cells and develop antagonists of PXR to sensitize cancer cells toward drug therapy. Three specific aims are proposed in this proposal. In the first aim, the potential activation of PXR by drugs commonly used in chemotherapy will be examined using biochemical and cellular assays. The regulation of gene expression of DMEs and efflux transporters by PXR in cancer and normal cells will be examined in the second specific aim using reporter gene assay for promoter activities, quantitative RT-PCR, PCR array, and biochemical assays of DMEs and efflux transporters. The functional role of PXR in drug sensitivity of tumor cells will be examined in the third specific aim through using syngenic tumor cells with difference only in the profiles of PXR activities or expression. The proposed studies will significantly advance our understanding about resistance of tumor cells toward chemotherapy and provide a potential avenue to improve the efficacy of cancer chemotherapy. PUBLIC HEALTH RELEVANCE: Multi-drug resistance is a significant barrier to effective cancer chemotherapy. Targeting a single drug metabolizing enzyme or efflux transporter has limited success in reversing multi-drug resistance. Pregnane X receptor (PXR) is a recently identified nuclear receptor that regulates the gene expression of drug metabolizing enzymes and efflux transporters. The goals of this proposal are to examine the activation of PXR by commonly used chemotherapeutics, to determine the regulation of gene expression of drug metabolizing or efflux proteins by PXR, and to define the functionality of PXR in the responses of tumor cells toward chemotherapy. The proposed studies will significantly advance our knowledge regarding multi-drug resistance of cancer and further provide a potential avenue to alleviate or reverse multi-drug resistance, a huge problem in cancer chemotherapy. [unreadable] [unreadable] [unreadable]