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  • Review Article
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Targeting liver X receptors in cancer therapeutics

Nature Reviews Cancer volume 15, pages 216–224 (2015)Cite this article

Subjects

Key Points

  • Members of the nuclear receptor (NR) superfamily of ligand-dependent transcription factors have key roles in a number of cancers and are highly druggable targets.

  • Liver X receptors (LXRs) are NRs that function as oxysterol sensors in metabolic tissues and immune cells. Synthetic LXR ligands have been developed for the treatment of atherosclerosis.

  • LXRs are expressed in a variety of cancers, and treatment with synthetic ligands has been shown to block tumour cell proliferation, tumorigenesis and metastasis in multiple cancer models.

  • Mechanisms of action of LXR ligands in cancer models include alterations in the expression and function of cell cycle, signal transduction, hormone response, and metabolic genes and pathways, and LXR ligands target both tumour cells and immune and stromal cells in the tumour microenvironment.

  • The current generation of synthetic LXR ligands was developed for treating heart and metabolic diseases, and so these ligands have not been optimized for cancer-related end points. In addition to identifying novel cancer-targeting ligands, available tissue-specific and receptor subtype-specific ligands may be effective in treating certain responsive cancers.

Abstract

Members of the nuclear receptor superfamily of ligand-dependent transcription factors carry out vital cellular functions and are highly druggable therapeutic targets. Liver X receptors (LXRs) are nuclear receptor family members that function in cholesterol transport, glucose metabolism and the modulation of inflammatory responses. There is now accumulating evidence to support the involvement of LXRs in a variety of malignancies and the potential efficacy of their ligands in these diseases. This Review summarizes the discovery and characterization of LXRs and their ligands, their effects and mechanisms in preclinical cancer models, and the future directions of basic and translational LXR research in cancer therapeutics.

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Figure 1: Structures of LXR, ligands and classical mechanism of action.
Figure 2: Composite model of potential mechanisms of action of LXR agonists and LXRs in human cancers.

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Acknowledgements

The authors thank X. Lou for preparing the image of the three-dimensional structure of the LXR–RXR heterodimer. This work was supported by grants to C.-Y.L. from Golfers Against Cancer and to J.-Å.G. from the Emerging Technology Fund of Texas (agreement 300-9-1958), the Robert A. Welch Foundation (E-0004) and the Swedish Science Council.

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  1. Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, 77204–5056, Texas, USA

    Chin-Yo Lin & Jan-Åke Gustafsson

  2. Department of Biosciences and Nutrition at NOVUM, Karolinska Institutet, SE-141 83, Huddinge, Sweden

    Jan-Åke Gustafsson

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Correspondence to Jan-Åke Gustafsson.

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Ligands

Small molecules that bind receptors and modulate their activity.

Ligand-binding domains

(LBDs). Conserved regions within the receptor molecule that bind ligands and alter molecular interactions and the activity of the receptor.

Phytochemicals

Chemicals found in plants that may affect health.

Steatosis

The abnormal accumulation of lipids in cells.

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Lin, CY., Gustafsson, JÅ. Targeting liver X receptors in cancer therapeutics. Nat Rev Cancer 15, 216–224 (2015). https://doi.org/10.1038/nrc3912

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