NR4A1 is an orphan nuclear receptor which can activate mTOR signaling and exhibits pro-oncogenic activity in cancer cell lines, regulates genes such as thioredoxin domain containing 5 and isocitrate dehydrogenase 1 that maintain low oxidative stress, and coactivates specificity protein 1 (Sp1)-regulated pro-survival and growth promoting genes. DIM-C-pPhCO2Me is a NR4A1 antagonist. DIM-C-pPhCO2Me exhibited anti-proliferative effect on ACHN cells and 786-O cells with IC50 values of 11.7μM and 13.4μM, respectively, as well as induced apoptosis in both cell lines at concentration of 20μM post 24h. DIM-C-pPhCO2Me at concentration of 20μM inhibited NR4A1-regulated expression of survivin, bcl-2 and EGFR, decreased expression of TXNDC5 and IDH1, and induced stress shown by increased CHOP, ATF4 and p-PERK. Inhibition of NR4A1 by 20μM DIM-C-pPhCO2Me activated induced sestrin 2, activated AMPKα and inhibited activation of mTOR and downstream kinases including phosphorylation of p70S6K, S6RP and 4EBP1. Treatment with DIM-C-pPhCO2Me at concentration of 15μM or 20μM for 12h induced ROS production in Rh30 and RD cells.
作用机制
DIM-C-pPhCO2Me decreased interactions of NR4A1, p300 and pol II with the GC-rich TXNDC5 and IDH1 promoters and resulted in some loss of Sp1 from the TXNDC5 promoter.[2]
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