Unknown,Transcriptomics,Genomics,Proteomics

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Antiproliferative effects and mechanisms of liver X receptor ligands in pancreatic ductal adenocarcinoma cells

ABSTRACT: This microarray is an analysis of differentially expressed genes in three pancreatic ductal adenocarcinoma cell lines treated with LXR-agonist GW 3965. We first report that GW 3965 has antiproliferative effects in three PDAC cell lines. This microarray was designed to identify key mechanisms of the antiproliferative effect of LXR agonists within pancreatic cancer cell lines. Total RNA obtained from BxPC-3, MIA-PaCa-2, and PANC-1 pancreatic cancer cells grown in culture treated GW 3965 or ethanol (vehicle control) for 72 hours.

ORGANISM(S): Homo sapiens

SUBMITTER: Nicholes Candelaria

PROVIDER: E-GEOD-51656 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Synthetic selective thyroid hormone (TH) receptor (TR) modulators (STRMs) exhibit beneficial effects on dyslipidemias in animals and humans and reduce obesity, fatty liver and insulin resistance in preclinical animal models. STRMs differ from native THs in preferential binding to the TR? subtype versus TR?, increased uptake into liver and reduced uptake into other tissues. However, selective modulators of other nuclear receptors (NRs) exhibit important gene-selective actions which have been attributed to differential effects on receptor conformation and dynamics and these effects can have profound influences in animals and humans. While there are suggestions that STRMs could exhibit such gene-specific actions, the extent to which these effects are actually observed in vivo has not been explored. Here, we show that saturating concentrations of the main active form of TH, triiodothyronine (T3), and the prototype STRM GC-1 induce identical gene-sets in livers of euthyroid and hypothyroid mice and a human cultured hepatoma cell line that only expresses TR?, HepG2. We find one case in which GC-1 exhibits a modest gene-specific reduction in potency versus T3, at angiopoietin-like factor 4 (ANGPTL4) in HepG2. Investigation of the latter effect confirms that GC-1 acts through TR? to directly induce this gene. However, this gene-selective GC-1 activity is not related to unusual T3 response element (TRE) sequence, unlike previously documented promoter-selective STRM actions. Together, our data suggest that T3 and GC-1 exhibit almost identical gene regulation properties and that gene-selective actions of GC-1 and similar STRMs will be subtle and rare. We treated 9-week old euthyroid male C57/Bl6 mice with vehicle or ligand (T3 or GC-1) by a single oral gavage (n=5 per treatment) and also performed a similar study in which mice were first made hypothyroid by two week feeding on iodine deficient diet (n=3-4 per treatment), analyzing mRNA 24h post treatment [Illumina]. We also treated HepG2 with vehicle or 10nM ligand (T3 or GC1; n=3 / treatment), analyzing mRNA 24h post treatment [Affymetrix].