Liver X receptor β activation induces pyroptosis of human and murine colon cancer cells

Cell Death Differ. 2014 Dec;21(12):1914-24. doi: 10.1038/cdd.2014.117. Epub 2014 Aug 15.

Abstract

Liver X receptors (LXRs) have been proposed to have some anticancer properties, through molecular mechanisms that remain elusive. Here we report for the first time that LXR ligands induce caspase-1-dependent cell death of colon cancer cells. Caspase-1 activation requires Nod-like-receptor pyrin domain containing 3 (NLRP3) inflammasome and ATP-mediated P2 × 7 receptor activation. Surprisingly, LXRβ is mainly located in the cytoplasm and has a non-genomic role by interacting with pannexin 1 leading to ATP secretion. Finally, LXR ligands have an antitumoral effect in a mouse colon cancer model, dependent on the presence of LXRβ, pannexin 1, NLRP3 and caspase-1 within the tumor cells. Our results demonstrate that LXRβ, through pannexin 1 interaction, can specifically induce caspase-1-dependent colon cancer cell death by pyroptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis*
  • Carrier Proteins / metabolism
  • Caspase 1 / metabolism
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / metabolism
  • Connexins / metabolism
  • Drug Screening Assays, Antitumor
  • Female
  • HCT116 Cells
  • HEK293 Cells
  • HT29 Cells
  • Humans
  • Hydrocarbons, Fluorinated / pharmacology
  • Liver X Receptors
  • Mice, Inbred BALB C
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Neoplasm Transplantation
  • Nerve Tissue Proteins / metabolism
  • Orphan Nuclear Receptors / agonists
  • Orphan Nuclear Receptors / metabolism*
  • Sulfonamides / pharmacology
  • Tumor Burden / drug effects

Substances

  • Antineoplastic Agents
  • Carrier Proteins
  • Connexins
  • Hydrocarbons, Fluorinated
  • Liver X Receptors
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Nerve Tissue Proteins
  • Orphan Nuclear Receptors
  • PANX1 protein, human
  • Sulfonamides
  • TO-901317
  • Adenosine Triphosphate
  • Caspase 1