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Research Articles: Therapeutics

A novel peroxisome proliferator–activated receptor ligand, MCC-555, induces apoptosis via posttranscriptional regulation of NAG-1 in colorectal cancer cells

¹ Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee and ² Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina

Requests for reprints: Seung Joon Baek, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996. Phone: 865-974-8216; Fax: 865-974-5616. E-mail: sbaek2{at}utk.edu

Apoptosis and/or differentiation induction caused by the peroxisome proliferator–activated receptor (PPAR) 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 PPAR-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 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. [Mol Cancer Ther 2006;5(5):1352–61]

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Received 12/16/05; revised 2/28/06; accepted 3/17/06.

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