Understanding the Expression, Function and Regulatory Mechanism of Liver X Receptor Genes in Human Prostate Cancer

Recently report from NIH in Taiwan indicated PC is up to the 7th leading cause of cancer-related death in Taiwan. Liver X receptors (LXR) are ligand-activated transcriptional factors that belong to the nuclear receptor superfamily. In liver cells, LXR are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXR agonists are effective for treatment of murine models of atherosclerosis, diabetes, and Alzheimer’s disease. Recent studies have indicated that LXR agonist (T0901317) suppressed proliferation of prostate cancer cell in vitro and treatment of mice with the LXR agonist T0901317 suppressed the growth of prostate tumor xenografts. LXR agonists appear to cause G1 cell cycle arrest in cells. Our preliminary studies also revealed that LXR agonists (T0901317 and GW3965) enhanced BTG2, an antiproliferation gene, gene expression which caused LNCaP and PC-3 cells arrested in G1/S phase. Although the precise mechanisms of LXR in the human prostate are still not well-know, previous reports have suggested a potential role of LXR signaling during prostate cancer progression. Interesting, our preliminary results indicated that T0901317 and GW3965 have contrary effect on prostate-specific antigen (PSA) gene expression. Increased glucose consumption is basic characteristic of malignant cells and is linked to energy production from glycolysis. Recent studies demonstrated that glucose is an endogenous LXR ligand and LXR as a transcriptional switch that intergrates hepatic glucose metabolism and fatty acid synthesis. Since the expression and function of LXR in human prostate are still unclarified, it will important and worth to identify the precise mechanisms of LXR agonists. The studies of this three-year proposal will (1) characterize the function of LXRs by using the LXRs knockdown and LXRs overexpression prostate cells line, (2). characterize the expression of LXRs in the human prostate, (3). understand the function and identify regulatory mechanisms of LXR agonists and polyphenol drugs in the cell proliferation and invasion of prostate carcinoma cells, and (4) understand the regulatory mechanisms of LXR on metabolism of prostate.

Project ID:PC10007-0377
External Project ID:NSC100-2320-B182-006