Targeting Liver X Receptors in Cancer Drug Discovery

Abstract

Liver X receptors (LXRs) are members of the nuclear receptor superfamily of ligand-dependent transcription factors. LXRα is predominantly expressed in metabolic tissues, whereas LXRβ is ubiquitously expressed. Upon ligand binding, they regulate the expression of target genes involved in lipid metabolism, cholesterol homeostasis, and immune responses, including those which function in pathways that are commonly reprogrammed during carcinogenesis. Known LXR ligands include oxysterols and natural and synthetic agonists which upregulate LXR transcriptional activity and target gene expression. Synthetic inverse agonists have also been identified that inhibit LXR activity. While both types of ligands have been shown to inhibit cancer cells and tumor growth either directly or indirectly by modulating the activities of stromal cells within the tumor microenvironment, they appear to target different aspects of cancer metabolism and other cancer hallmarks, including immune evasion. This review summarizes the characterization of LXRs and their ligands and their mechanisms of action in cancer models and discusses the future directions for translating these discoveries into novel cancer therapeutics.