Antiproliferative effect of liver X receptor agonists on LNCaP human prostate cancer cells

Cancer Res. 2004 Nov 1;64(21):7686-9. doi: 10.1158/0008-5472.CAN-04-2332.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anticholesteremic Agents / pharmacology*
  • Cell Cycle Proteins / metabolism
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p27
  • DNA-Binding Proteins
  • Humans
  • Hydrocarbons, Fluorinated
  • Liver X Receptors
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Orphan Nuclear Receptors
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / pathology
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, Cytoplasmic and Nuclear / physiology
  • Sulfonamides
  • Tumor Suppressor Proteins / metabolism

Substances

  • Anticholesteremic Agents
  • Cdkn1b protein, mouse
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Hydrocarbons, Fluorinated
  • Liver X Receptors
  • NR1H3 protein, human
  • Nr1h3 protein, mouse
  • Orphan Nuclear Receptors
  • Receptors, Cytoplasmic and Nuclear
  • Sulfonamides
  • T0901317
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27