Modulation of liver X receptor signaling as a prevention and therapy for colon cancer

Abstract

Liver X receptors (LXRα and LXRβ) are members of the nuclear receptor family and 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. Recently we and other groups observed that LXR agonists suppressed proliferation of multiple human cancer cell lines in vitro as well as suppressed the growth and progression of prostate tumor xenografts in nude mice. LXR agonists appear to cause G1 cell cycle arrest in cancer cells by reducing the protein expression level of Skp2, cyclin A2, cyclin D1, and the phosphorylation of Rb, while increasing the protein expression level of cell cycle inhibitor p27 Kip1 and p53. LXR agonist also suppressed the oncogenic activity of β-catenin, an important regulator in Wnt signaling, as well as the proliferation in human colon cancer cells. Phytosterols, the plant equivalent of mammalian cholesterol, have been shown to be agonists for LXRs. Intake of phytosterol-rich diets reduced the incidence of colon cancer. We therefore propose that activation of LXR signaling via treatment with LXR agonists or intake of phytosterols-rich diets can reduce the incidence and suppress the tumor growth of colon cancer.