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Colon cancer cells DLD1 cells incubated with kynurenine, TCDD, or CH223191 for 1 hour

ABSTRACT: The ligand-activated transcription factor Aryl Hydrocarbon Receptor (AHR) regulates cellular detoxification, proliferation, and immune evasion in a range of cell types and tissues, including cancer cells. In this study, we used RNA-seq to identify the signature of AHR target genes regulated by the pollutant 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and the endogenous ligand kynurenine (Kyn), a tryptophan-derived metabolite. This approach identified a signature of six genes (CYP1A1, ALDH1A3, ABCG2, ADGFR1, and SCIN) as commonly activated by endogenous or exogenous ligands of AHR in multiple colon cancer cell lines. Among these, the actin-severing protein Scinderin (SCIN) was necessary for cell proliferation; SCIN downregulation limited cell proliferation and its expression increased it. SCIN expression is elevated in a subset of colon cancer patient samples, which also contain elevated β-catenin levels. Remarkably, SCIN expression promotes nuclear translocation of β-catenin and activates the WNT pathway. Our study identified a new mechanism for adhesion-mediated signaling in which SCIN, likely via its ability to alter the actin cytoskeleton, facilitates the nuclear translocation of β-catenin.

ORGANISM(S): Homo sapiens

PROVIDER: GSE212795 | GEO | 2023/06/12

REPOSITORIES: GEO

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Project description:Indoxyl sulfate (IS) is a uremic toxin and ligand of the aryl-hydrocarbon receptor (Ahr), a transcriptional regulator. Elevated serum IS may contribute to the progression of kidney disease. Therefore, we assessed mouse podocyte damage mediated by IS. Ahr was predominantly localized to the podocyte nucleus in vivo and in vitro. In isolated glomeruli, IS-exposure for 2 – 24 h induced Cyp1a1 expression, the most sensitive biomarker of Ahr activation. Mice exposed to IS for 4–8 weeks exhibited microalbuminuria, and mild glomerular injury characterized by ischemic changes, partial podocyte foot process effacement, as well as vascular and tubulointerstitial damage. Chronically IS-exposed kidneys exhibited decreased mRNA, decreased protein levels, and altered staining patterns for podocin, synaptopodin, and non-muscle myosin IIA (Myh9). Immortalized podocytes, upon differentiation, exhibited Ahr nuclear translocation beginning 30 min after 1 mM IS-exposure. At 2 h, there was a dose-dependent decrease in podocyte mRNA expression of WT1, Podxl, Snypo, Myh9, Actn4, and Cd2ap. After 24 h of exposure to IS, podocytes were smaller, had fewer actin/Myh9 fibers, and decreased viability. Ahr-RNAi decreased mRNA expression of podocyte-specific proteins and inhibited Cyp1a1 induction by IS-exposure. Combinations of Ahr-RNAi and IS-exposure further decreased Myh9 expression. In immortalized human podocytes, IS treatment caused cell injury, decreased mRNA expression of podocyte-specific proteins, integrins, collagens, cytoskeletal proteins, and bone morphogenetic proteins, and increased cytokine and chemokine expression. Thus, chronic IS-exposure causes glomerular damage by activating Ahr, altering podocyte function, differentiation, and morphology, and inducing a pro-inflammatory phenotype. Podocyte cells treated with Indoxyl sulfate, a uremic toxin and aryl-hydrocarbon receptor ligand, mediates progressive glomerular disease by damaging podocytes Human podocyte cell line treated with or without 3-Indoxyl sulfate (1mM/0.1%DMSO) in three replications

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Colon cancer cells DLD1 cells incubated with kynurenine, TCDD, or CH223191 for 1 hour

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