OBJECTIVES: NR4A1 is overexpressed in many solid tumors, and the objectives of this study were to investigate the expression and functional role of this receptor in endometrial cancer cells and demonstrate that NR4A1 antagonist inhibit mTOR. We conclude that TMS is a Car ligand with limited effects on hepatocyte proliferation, likely due to promoting apoptosis in mouse hepatic cells, while controlling Car target genes involved in xenobiotic and endobiotic metabolism. In murine hepatic AML12 cells, we confirmed a Car-independent proapoptotic effect of TMS. TMS did not increase liver weight and had no significant effect on Ki67 and Pcna labeling indices in mouse liver in vivo. TMS did not change or down-regulate genes involved in liver proliferation or apoptosis such as Mki67, Foxm1, Myc, Mcl1, Pcna, Bcl2, or Mdm2, which were up-regulated by another Car ligand TCPOBOP. TMS up-regulated Car target genes Cyp2b10, Cyp2c29 and Cyp2c55 mRNAs, but down-regulated expression of genes involved in gluconeogenesis and lipogenesis. Unexpectedly, we identified TMS as a murine CAR agonist in reporter gene experiments, in mouse hepatocytes, and in C57BL/6 mice in vivo. We studied whether TMS inhibits mouse Car to protect from the PB-induced tumorigenesis. Recently, trans-3,4,5,4ยด-tetramethoxystilbene(TMS), a potential anticancer drug (DMU-212), have been shown to alleviate N-nitrosodiethylamine/phenobarbital-induced liver carcinogenesis. CAR activators, including phenobarbital, are considered rodent non-genotoxic carcinogens. The constitutive androstane receptor(CAR) activation is connected with mitogenic effects leading to liver hyperplasia and tumorigenesis in rodents.
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