t0901317 and Colonic-Neoplasms

Liver X receptor (LXR) agonists inhibit various types of tumor growth and have been applied to preclinical research. In colon cancer cells, LXR agonists induce pyroptotic cell death through the predominant cytoplasmic localisation of LXRβ. In the present study, we determined whether tumor cell death induced by LXR agonists in colon cancer cells could elicit immunogenic cell death (ICD). LXR agonist-treated-colon cancer cells exhibited translocation of calreticulin (CRT) and release of HMGB1 and ATP into the medium. Expression levels of CRT and HMGB1 were also increased in T0901317-treated Balb/c mice. Furthermore, compared with control mice, mice vaccinated with T0901317-treated CT26 cells showed reduced tumor volumes and protection against a challenge with live tumor cells. Inhibition of CRT or HMGB1 expression in CT26 cells abolished this protection in Balb/c mice. In conclusion, the LXR agonist T0901317 induces ICD in colon cancer cells. CRT exposure and HMGB1 release play a critical role in the immunogenicity of this treatment.

Topics: Animals; Antineoplastic Agents; Calreticulin; Cell Death; Cell Line, Tumor; Colonic Neoplasms; Female; HCT116 Cells; HMGB1 Protein; Humans; Hydrocarbons, Fluorinated; Liver Neoplasms; Liver X Receptors; Mice; Mice, Inbred BALB C; Mice, Nude; Sulfonamides

Increasing evidence indicates that Liver X Receptors (LXRs) have some anticancer properties. We recently demonstrated that LXR ligands induce colon cancer cell pyroptosis through an LXRβ-dependent pathway. In the present study, we showed that human colon cancer cell lines presented differential cytoplasmic localizations of LXRβ. This localization correlated with caspase-1 activation and cell death induction under treatment with LXR ligand. The association of LXRβ with the truncated form of RXRα (t-RXRα) was responsible for the sequestration of LXRβ in the cytoplasm in colon cancer cells. Moreover t-RXRα was not expressed in normal colon epithelial cells. These cells presented a predominantly nuclear localization of LXRβ and were resistant to LXR ligand cytotoxicity. Our results showed that predominant cytoplasmic localization of LXRβ, which occurs in colon cancer cells but not in normal colon epithelial cells, allowed LXR ligand-induced pyroptosis. This study strengthens the hypothesis that LXRβ could be a promising target in cancer therapy.

Topics: Caspase 1; Cell Line; Cell Line, Tumor; Colon; Colonic Neoplasms; Cytoplasm; Enzyme Activation; Epithelial Cells; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Hydrocarbons, Fluorinated; Intestinal Mucosa; Ligands; Liver X Receptors; Orphan Nuclear Receptors; Retinoid X Receptor alpha; Sulfonamides

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.

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