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

Liver X receptors (LXRs; LXRα and 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. 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. Study 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 in vitro studies also revealed that LXR agonists (T0901317 and GW3965) enhanced gene expression of B cell translocation gene 2 (BTG2), an antiproliferation gene, which caused LNCaP and PC-3 cells arrested in G1/S phase. Interestingly, our results also revealed that T0901317 and GW3965 have contrary effect on prostate-specific antigen (PSA) gene expression. Studies of our preliminary experiments indicated that LXR agonists affected the expression of target genes concerning cellular growth, PSA, tumorigenesis, and metabolism via either LXRα- or LXR-dependent pathway. Increased glucose consumption is basic characteristic of malignant cells and is linked to energy production from glycolysis and lipogenesis. 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. Our preliminary data indicated that glucose and LXR agonists enhanced the expression of fatty acid synthase. It seems that LXR agonists have divergent effects on tumorigenesis and metabolism. Since the expression and function of LXR in human prostate are still unclarified, it is important and worthy to understand the expression of LXR in the prostate tissues and to identify the precise mechanisms of LXR agonists. The aims of this three-year proposal are going to (1) characterize the function of LXRs (LXRα and LXR) in vitro and in xenograph animal studies by cloning the LXRs knockdown or ectopic-overexpressed LXRs prostate carcinoma cell lines, (2). characterize the correlation between the expression of LXRs and pathologic stage in the human prostate tissue, (3). understand the function of LXR agonists in the cell proliferation and invasion of prostate carcinoma cells and identify the downstream target genes and their regulatory mechanisms, and (4). understand the regulatory mechanisms of LXR agonists on the metabolism of the human prostate carcinoma cells.

Project ID:PC10108-0899
External Project ID:NSC101-2320-B182-002