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.