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]
DIM-C-pPhCO2Me 细胞实验
Cell Line
Concentration
Treated Time
Description
References
786-O cells
0–20μM
24 hours
Inhibited cell proliferation and induced apoptosis
PLoS One. 2015 Jun 2;10(6):e0128308
ACHN cells
0–20μM
24 hours
Inhibited cell proliferation and induced apoptosis
PLoS One. 2015 Jun 2;10(6):e0128308
MCF-7 cells
20 μM
24 hours
To investigate the effect of DIM-C-pPhCO2Me on MCF-7 cell migration, results showed that the compound significantly inhibited cell migration.
Mol Cell Biol. 2016 Apr 15;36(9):1383-94
MDA-MB-231 cells
20 μM
24 hours
To investigate the effect of DIM-C-pPhCO2Me on MDA-MB-231 cell migration, results showed that the compound significantly inhibited cell migration.
Mol Cell Biol. 2016 Apr 15;36(9):1383-94
SKBR3 cells
20 μM
24 hours
To investigate the effect of DIM-C-pPhCO2Me on SKBR3 cell migration, results showed that the compound significantly inhibited cell migration.
Mol Cell Biol. 2016 Apr 15;36(9):1383-94
SW480 cells
15 and 20 μM
24 hours
Decreased β1-integrin expression, inhibited cell migration and adhesion
Mol Carcinog. 2017 Sep;56(9):2066-2075
RKO cells
15 and 20 μM
24 hours
Decreased β1-integrin expression, inhibited cell migration and adhesion
Mol Carcinog. 2017 Sep;56(9):2066-2075
MiaPaCa2 cells
15 and 20 μM
24 hours
Decreased β1-integrin expression, inhibited cell migration and adhesion
Mol Carcinog. 2017 Sep;56(9):2066-2075
L3.6pL cells
15 and 20 μM
24 hours
Decreased β1-integrin expression, inhibited cell migration and adhesion
Mol Carcinog. 2017 Sep;56(9):2066-2075
Panc1 cells
15 and 20 μM
24 hours
Decreased β1-integrin expression, inhibited cell migration and adhesion
Mol Carcinog. 2017 Sep;56(9):2066-2075
RD cells
15 μM
24 to 72 hours
To investigate the inhibitory effect of DIM-C-pPhCO2Me on the proliferation of RD cells, results showed that prolonged exposure time enhanced the inhibitory effect.
Oncotarget. 2016 May 24;7(21):31257-69
Rh30 cells
5 to 15 μM
24 hours
To investigate the inhibitory effect of DIM-C-pPhCO2Me on the proliferation of Rh30 cells, results showed that the compound effectively inhibited cell proliferation.
Oncotarget. 2016 May 24;7(21):31257-69
DIM-C-pPhCO2Me 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NSG mice
Breast cancer xenograft model
Oral gavage
20 or 40 mg/kg/day
Every other day for 50 days
To evaluate the inhibitory effect of NR4A1 antagonist on tumor growth, results showed NR4A1-i caused tumor shrinkage, accompanied by increased FOS expression, elevated DNA damage marker γH2AX, and reduced Ki-67 expression
Mol Cell. 2021 Oct 7;81(19):4041-4058. e15
BALB/c nude mice
MDA-MB-231 xenograft model
40 mg/kg/day
Daily administration, duration
To investigate the effect of DIM-C-pPhCO2Me on MDA-MB-231 xenograft tumors, results showed that the compound significantly inhibited tumor growth.
Mol Cell Biol. 2016 Apr 15;36(9):1383-94
Athymic nude mice
ACHN cell xenograft model
Oral gavage
30 mg/kg/day
Once daily for 50 days
Inhibited tumor growth
PLoS One. 2015 Jun 2;10(6):e0128308
Nude mice
Rh30 xenograft model
Oral gavage
40 mg/kg/d
Every second day for 20 days
To investigate the inhibitory effect of DIM-C-pPhCO2Me on the growth of Rh30 xenograft tumors, results showed that the compound significantly inhibited tumor growth.
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