Although therapeutic effects of the peroxisome proliferator-activated receptor gamma (PPAR-) agonists rosiglitazone and pioglitazone against Cushing's disease have been reported, their effects are still controversial and inconsistent. We therefore examined the effects of a novel PPAR- agonist, MEKT1, on expression/ACTH secretion using murine corticotroph-derived AtT20 cells and compared its effects with those of rosiglitazone and pioglitazone. AtT20 cells were treated with either 1 nM~10 M MEKT1, rosiglitazone, or pioglitazone for 24 hours. Thereafter, their effects on proopiomelanocortin gene mRNA expression were studied by qPCR and the promoter (-703/+58) activity was demonstrated by luciferase assay. mRNA expression and promoter activity were significantly inhibited by MEKT1 at 10 M compared to rosiglitazone and pioglitazone. SiRNA-mediated PPAR- knockdown significantly abrogated MEKT1-mediated mRNA suppression. ACTH secretion from AtT20 cells was also significantly inhibited by MEKT1. Deletion/point mutant analyses of promoter indicated that the MEKT1-mediated suppression was mediated via NurRE, TpitRE, and NBRE at -404/-383, -316/-309, and -69/-63, respectively. Moreover, MEKT1 significantly suppressed , , and mRNA expression. MEKT1 also was demonstrated to inhibit the protein-DNA interaction of Nur77/Nurr1-NurRE, Tpit-TpitRE, and Nur77-NBRE by ChIP assay. Taken together, it is suggested that MEKT1 could be a novel therapeutic medication for Cushing's disease.
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| http://dx.doi.org/10.1155/2018/5346272 | DOI Listing |
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