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Liver X receptor ligand cytotoxicity in colon cancer cells and not in normal colon epithelial cells depends on LXR? subcellular localization.

ABSTRACT: 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 LXR?-dependent pathway. In the present study, we showed that human colon cancer cell lines presented differential cytoplasmic localizations of LXR?. This localization correlated with caspase-1 activation and cell death induction under treatment with LXR ligand. The association of LXR? with the truncated form of RXR? (t-RXR?) was responsible for the sequestration of LXR? in the cytoplasm in colon cancer cells. Moreover t-RXR? was not expressed in normal colon epithelial cells. These cells presented a predominantly nuclear localization of LXR? and were resistant to LXR ligand cytotoxicity. Our results showed that predominant cytoplasmic localization of LXR?, which occurs in colon cancer cells but not in normal colon epithelial cells, allowed LXR ligand-induced pyroptosis. This study strengthens the hypothesis that LXR? could be a promising target in cancer therapy.

SUBMITTER: Courtaut F

PROVIDER: S-EPMC4694942 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Liver X receptor ligand cytotoxicity in colon cancer cells and not in normal colon epithelial cells depends on LXRβ subcellular localization.

Courtaut Flavie F Derangère Valentin V Chevriaux Angélique A Ladoire Sylvain S Cotte Alexia K AK Arnould Laurent L Boidot Romain R Rialland Mickaël M Ghiringhelli François F Rébé Cédric C

Oncotarget 20150901 29

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 ...[more]

PMID: 26450852

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Project description:The extracellular matrix (ECM) plays crucial roles in tissue homeostasis. Abnormalities in ECM composition are associated with pathological conditions, such as fibrosis and cancer. These ECM alterations are sensed by the epithelium and can influence its behavior through crosstalk with other mechanosensitive complexes, including the adherens junctions (AJs). We have previously shown that the AJs, through their component PLEKHA7, recruit the RNAi machinery to regulate miRNA levels and function. We have particularly shown that the junctional localization of RNAi components is critical for their function. Here, we investigated whether different ECM substrates can influence the junctional localization of RNAi complexes. To do this, we plated colon epithelial Caco2 cells on four key ECM substrates found in the colon under normal or pathogenic conditions, namely laminin, fibronectin, collagen I, and collagen IV, and we examined the subcellular distribution of PLEKHA7, and of the key RNAi components AGO2 and DROSHA. Fibronectin and collagen I negatively impacted the junctional localization of PLEKHA7, AGO2, and DROSHA when compared to laminin. Furthermore, fibronectin, collagen I, and collagen IV disrupted interactions of AGO2 and DROSHA with their essential partners GW182 and DGCR8, respectively, both at AJs and throughout the cell. Combinations of all substrates with fibronectin also negatively impacted junctional localization of PLEKHA7 and AGO2. Additionally, collagen I triggered accumulation of DROSHA at tri-cellular junctions, while both collagen I and collagen IV resulted in DROSHA accumulation at basal areas of cell-cell contact. Altogether, fibronectin and collagens I and IV, which are elevated in the stroma of fibrotic and cancerous tissues, altered localization patterns and disrupted complex formation of PLEKHA7 and RNAi components. Combined with our prior studies showing that apical junctional localization of the PLEKHA7-RNAi complex is critical for regulating tumor-suppressing miRNAs, this work points to a yet unstudied mechanism that could contribute to epithelial cell transformation.

Dataset Information

Liver X receptor ligand cytotoxicity in colon cancer cells and not in normal colon epithelial cells depends on LXR? subcellular localization.

Publications

Liver X receptor ligand cytotoxicity in colon cancer cells and not in normal colon epithelial cells depends on LXRβ subcellular localization.

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