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Updated: Aug 21, 2026
The Influence of Liver Resection on Intrahepatic Tumor Growth
Published on: April 9, 2016
Antiproliferative effect of liver X receptor agonists on LNCaP human prostate cancer cells
Junichi Fukuchi1, John M Kokontis, Richard A Hiipakka
1The Ben May Institute for Cancer Research and The Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois 60637, USA.
Abstract:
Liver X receptors function as central transcriptional regulators for lipid homeostasis, for which agonists have been developed as potential drugs for treatment of cardiovascular diseases and metabolic syndromes. Because dysregulation of lipid metabolism has been implicated in sex hormone-dependent cancers, we investigated the effect of liver X receptor agonists on prostate and breast cancer cell proliferation. Treatment of human prostate cancer LNCaP cell lines with the synthetic liver X receptor agonist T0901317 decreased the percentage of S-phase cells in a dose-dependent manner and increased the expression of cyclin-dependent kinase inhibitor p27(Kip-1) (p27). Knockdown of p27 by RNA interference blocks T0901317-induced growth inhibition, suggesting that p27 expression plays a crucial role in this signaling. Liver X receptor agonists also inhibited the proliferation of other prostate and breast cancer cell lines. The level of liver X receptor alpha expression correlated directly with sensitivity to growth inhibition by liver X receptor agonists. Retroviral expression of liver X receptor alpha in human breast cancer MDA-MB435S cells, which express low levels of endogenous liver X receptors and are insensitive to T0901317, sensitized these cells to T0901317. Consistent with our observations in LNCaP cells, T0901317 induces dramatic up-regulation of p27 in liver X receptor alpha-overexpressing MDA-MB435S cells. Furthermore, oral administration of T0901317 inhibited the growth of LNCaP tumors in athymic nude mice. Based on these results, modulation of the liver X receptor signaling pathway is a new target for controlling tumor cell proliferation; therefore, liver X receptor agonists may have utility as antitumorigenic agents.
Insights
Liver X receptor agonists, like T0901317, inhibit prostate and breast cancer cell proliferation by upregulating p27 expression. This pathway shows promise for developing new antitumorigenic agents.
Area of Science:
- Molecular biology
- Oncology
- Endocrinology
Background:
- Liver X receptors (LXRs) are key regulators of lipid metabolism.
- Dysregulated lipid metabolism is linked to sex hormone-dependent cancers.
- LXR agonists are explored for cardiovascular and metabolic diseases.
Purpose of the Study:
- To investigate the impact of LXR agonists on prostate and breast cancer cell proliferation.
- To elucidate the role of p27 in LXR agonist-mediated growth inhibition.
- To assess the potential of LXR agonists as antitumorigenic agents.
Main Methods:
- Treatment of human prostate (LNCaP) and breast cancer cell lines with synthetic LXR agonist T0901317.
- Analysis of cell cycle progression (S-phase percentage) and p27(Kip-1) expression.
- RNA interference for p27 knockdown and retroviral expression of LXR alpha.
- In vivo studies using LNCaP tumor xenografts in athymic nude mice.
Main Results:
- T0901317 decreased S-phase cells and increased p27 expression in LNCaP cells, with p27 knockdown blocking this effect.
- LXR agonists inhibited proliferation across various prostate and breast cancer cell lines.
- Sensitivity to LXR agonists correlated with LXR alpha expression levels.
- Overexpression of LXR alpha sensitized resistant cells and increased p27.
- T0901317 inhibited LNCaP tumor growth in vivo.
Conclusions:
- Modulating the LXR signaling pathway is a novel strategy for controlling tumor cell proliferation.
- LXR agonists demonstrate potential as effective antitumorigenic agents for hormone-dependent cancers.
