Antiproliferative effects and mechanisms of liver X receptor ligands in pancreatic ductal adenocarcinoma cells

PLoS One. 2014 Sep 3;9(9):e106289. doi: 10.1371/journal.pone.0106289. eCollection 2014.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is difficult to detect early and is often resistant to standard chemotherapeutic options, contributing to extremely poor disease outcomes. Members of the nuclear receptor superfamily carry out essential biological functions such as hormone signaling and are successfully targeted in the treatment of endocrine-related malignancies. Liver X receptors (LXRs) are nuclear receptors that regulate cholesterol homeostasis, lipid metabolism, and inflammation, and LXR agonists have been developed to regulate LXR function in these processes. Intriguingly, these compounds also exhibit antiproliferative activity in diverse types of cancer cells. In this study, LXR agonist treatments disrupted proliferation, cell-cycle progression, and colony-formation of PDAC cells. At the molecular level, treatments downregulated expression of proteins involved in cell cycle progression and growth factor signaling. Microarray experiments further revealed changes in expression profiles of multiple gene networks involved in biological processes and pathways essential for cell growth and proliferation following LXR activation. These results establish the antiproliferative effects of LXR agonists and potential mechanisms of action in PDAC cells and provide evidence for their potential application in the prevention and treatment of PDAC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Adult
  • Aged
  • Antineoplastic Agents / pharmacology*
  • Benzoates / pharmacology*
  • Benzylamines / pharmacology*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Ligands
  • Liver X Receptors
  • Male
  • Microarray Analysis
  • Middle Aged
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Orphan Nuclear Receptors / agonists
  • Orphan Nuclear Receptors / genetics*
  • Orphan Nuclear Receptors / metabolism
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Signal Transduction

Substances

  • Antineoplastic Agents
  • Benzoates
  • Benzylamines
  • GW 3965
  • Ligands
  • Liver X Receptors
  • Neoplasm Proteins
  • Orphan Nuclear Receptors
  • Deoxycytidine
  • gemcitabine

Grant support

This work was supported by an award from Golfers Against Cancer. The Center for Nuclear Receptors and Cell Signaling at the University of Houston is supported by the State of Texas Emerging Technologies Fund (grant number 300-9-1958). No individual employed or contracted by the funders (other than the named authors) played any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.