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- W1978125763 abstract "Apoptosis and/or differentiation induction caused by the peroxisome proliferator-activated receptor gamma (PPARgamma) ligand is a promising approach to cancer therapy. The thiazolidinedione derivative MCC-555 has an apoptotic activity in human colorectal cancer cells, accompanied by up-regulation of a proapoptotic nonsteroidal anti-inflammatory drug-activated gene (NAG-1) in a PPARgamma-independent manner. Treatment with MCC-555 resulted in the induction of NAG-1 expression and apoptosis in HCT-116 cells. Down-regulation of NAG-1 by small interfering RNA suppressed MCC-555-induced apoptosis. MCC-555 was found to affect NAG-1 mRNA stability. To further define the underlying mechanism of RNA stability affected by MCC-555, we cloned the 3'-untranslated region (3'UTR) of human NAG-1 mRNA, which contains four copies of an AU-rich element (ARE), downstream from the luciferase gene. The reporter activity was reduced to approximately 70% by inserting the 3'UTR. In addition, deletion of ARE sequences in the 3'UTR or MCC-555 treatment substantially restored activity. This effect of MCC-555 on the ARE-mediated mRNA degradation was inhibited by extracellular signal-regulated kinase (ERK) pathway inhibitors. Subsequently, rapid phosphorylation of ERK1/2 by MCC-555 treatment was detected. Moreover, ERK small interfering RNA suppressed MCC-555-induced NAG-1 expression. These results suggest that ARE sequences in the 3'UTR of the NAG-1 gene contribute to mRNA degradation and ERK1/2 phosphorylation is responsible for the stabilization of NAG-1 mRNA. These findings may provide a novel explanation for the antitumorigenic and/or proapoptotic action of MCC-555 in human colorectal cancer and the ability of pharmacologic approaches to be used against diseases caused by alterations of RNA stability." @default.
- W1978125763 created "2016-06-24" @default.
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- W1978125763 date "2006-05-01" @default.
- W1978125763 modified "2023-10-10" @default.
- W1978125763 title "A novel peroxisome proliferator–activated receptor γ ligand, MCC-555, induces apoptosis via posttranscriptional regulation of NAG-1 in colorectal cancer cells" @default.
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- W1978125763 doi "https://doi.org/10.1158/1535-7163.mct-05-0528" @default.
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