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
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism
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Animals
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Antineoplastic Agents / pharmacology
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Apoptosis*
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Carrier Proteins / metabolism
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Caspase 1 / metabolism
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Colonic Neoplasms / drug therapy
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Colonic Neoplasms / metabolism
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Connexins / metabolism
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Drug Screening Assays, Antitumor
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Female
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HCT116 Cells
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HEK293 Cells
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HT29 Cells
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Humans
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Hydrocarbons, Fluorinated / pharmacology
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Liver X Receptors
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Mice, Inbred BALB C
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NLR Family, Pyrin Domain-Containing 3 Protein
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Neoplasm Transplantation
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Nerve Tissue Proteins / metabolism
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Orphan Nuclear Receptors / agonists
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Orphan Nuclear Receptors / metabolism*
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Sulfonamides / pharmacology
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Tumor Burden / drug effects
Substances
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Antineoplastic Agents
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Carrier Proteins
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Connexins
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Hydrocarbons, Fluorinated
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Liver X Receptors
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NLR Family, Pyrin Domain-Containing 3 Protein
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NLRP3 protein, human
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Nerve Tissue Proteins
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Orphan Nuclear Receptors
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PANX1 protein, human
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Sulfonamides
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T0901317
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Adenosine Triphosphate
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Caspase 1