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

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 Â 7 receptor activation. Surprisingly, LXRb 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 LXRb, pannexin 1, NLRP3 and caspase-1 within the tumor cells. Our results demonstrate that LXRb, through pannexin 1 interaction, can specifically induce caspase-1-dependent colon cancer cell death by pyroptosis.

Transcriptional and non-transcriptional roles of LXRs in cancer cells

“…However most of the experiments were performed on HCT116 infected with AdVP16LXRα [7] . We also noticed little effects of LXR agonists on apoptosis, but in our hands the majority of cell death induced by these ligands, involve a cell membrane permeabilization and caspase-1 activation [15] . Second, the cell type and the expression/localization of LXRα or LXRβ can dictate the incidence of LXR agonist treatment.…”

“…ATP release, caspase-1 activation (and to a lesser extent late caspase-7 activation), chromatin fragmentation, cell swelling until becoming a balloon-shaped vesicle around the nucleus and membrane permeabilization. Moreover we did not observe any caspase-3, -8 or -9 activation in our settings [15] . Maybe the higher concentrations of LXR ligands used, can explain some of the differences observed with other studies.…”

“…ABCA1 or SREBF1) expression was increased only from 24 hours in these cells. In addition the transcription inhibitor actinomycin D had no effect on LXR-dependent cell death [15] .…”

“…No effect CD [15] described to transcriptionnaly regulate the expression of these cell cycle regulators [10] . The induction of p53 expression and activation was also proposed to be responsible for the effects of LXRs on cell cycle [6] .…”

Liver X receptors as potential targets for cancer therapeutics (Review)

“…More importantly, LXRs also serve non-genomic roles due to the differential cytoplasmic localization of LXRβ. LXRβ is predominantly located in the cytoplasm of colon cancer cells and induces pyroptosis when bound by ligand (26,27). Previously, a study revealed that LXR activation leads to cell cycle arrest in colon cancer cell lines.…”