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

Abstract

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 antiinflammatory 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 f70% 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]

Nonsteroidal Anti-inflammatory Drug-activated Gene (NAG-1/GDF15) Expression Is Increased by the Histone Deacetylase Inhibitor Trichostatin A

“…The cDNA has been cloned by six different groups (as known as MIC-1, PDF, GDF-15, PLAB, and PTGFB). The previous investigations on the regulation of NAG-1 expression revealed complex mechanisms that can be modulated by a number of drugs and chemicals: cyclooxygenase inhibitors (3), dietary agents (4 -6), PPAR agonist (7)(8)(9), and anti-cancer drugs (10). Moreover, NAG-1 is induced by several nonsteroidal anti-inflammatory drugs and other drugs known to have anti-tumorigenic and pro-apoptotic activities (11,12).…”

Molecular characterisation of canine nonsteroidal anti-inflammatory drug-activated gene (NAG-1)

“…PPARγ ligands have been characterised as having anti-tumorigenic effects in numerous types of human cancer showing induction of apoptosis and NAG-1 expression (Yamaguchi et al, 2006a). To see if the same phenomenon occurred in canine osteosarcoma, CCL-183 cells were treated with MCC-555 and rosiglitazone, both of which induce NAG-1 expression in human colorectal cancer cells.…”

“…NAG-1 is up-regulated by a number of anti-tumorigenic compounds in addition to NSAIDs, including peroxisome proliferator-activated receptor γ (PPARγ) ligands (Baek et al, 2003;2004b;Yamaguchi et al, 2006a), phosphatidylinositol 3-kinase inhibitor (Yamaguchi et al, 2004) and chemopreventive dietary compounds, such as resveratrol (Baek et al, 2002a), indole-3-carbinol , conjugated linoleic acid (Lee et al, 2006) and epicatechin gallate (Baek et al, 2004a), as well as anti-inflammatory plant extracts (Yamaguchi et al, 2006b). Interestingly, induction of NAG-1 by these compounds occurs by multiple mechanisms at the levels of transcription and post-transcription.…”

A novel anticancer effect of Astragalus saponins: Transcriptional activation of NSAID‐activated gene

“…6 Nonsteroidal anti-inflammatory drug (NSAID)-activated gene (NAG-1) is a novel therapeutic target which contributes to the antitumorigenic and proapoptotic effects in various cancer cells. [7][8][9][10] As previously reported, the anticancer activities of several compounds obtained from natural sources could be associated with NAG-1 induction. 7,[11][12][13] Initially, NAG-1 was found to be induced in a p53-dependent manner and therefore considered as a biomarker for p53 activation.…”