Proteasome inhibitor MG132 induces NAG-1/GDF15 expression through the p38 MAPK pathway in glioblastoma cells

Abstract

The expression of nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) is regulated by the p53 and Egr-1 tumor suppressor pathways. Many anti-cancer drugs and chemicals induce NAG-1 expression, but the mechanisms are not fully understood. Transgenic mice expressing human NAG-1 are resistant to intestinal and prostate cancer, suggesting that NAG-1 is a tumor suppressor. Proteasome inhibitors exhibit anti-glioblastoma activities in preclinical studies. Here, we show that the proteasome inhibitors MG132 and bortezomib induced NAG-1 expression and secretion in glioblastoma cells. MG132 increased NAG-1 expression through transcriptional and post-transcriptional mechanisms. At the transcriptional level, the induction of NAG-1 required the −133 to +41 bp region of the promoter. At post-transcriptional levels, MG132 stabilized NAG-1 mRNA by increasing the half-life from 1.5 h to > 8 h. Because of the dramatic increase in mRNA stability, this is likely the major contributor to MG132-mediated NAG-1 induction. Further probing into the mechanism revealed that MG132 increased phosphorylation of the p38 MAPK pathway. Consequently, inhibiting p38 phosphorylation blocked activation of the NAG-1 promoter and decreased mRNA stability, indicating that p38 MAPK activation mediates both MG132-dependent promoter activation and mRNA stabilization of NAG-1. We propose that the induction of NAG-1 by p38 MAPK is a potential contributor to the anti-glioblastoma activity of proteasome inhibitors.

Anti-tumoral Effects of miR-3189-3p in Glioblastoma

“…Expression of GDF15 and miR-3189-3p Is Increased after Fenofibrate Treatment-Previous reports have demonstrated that GDF15 expression is induced following treatment by a variety of chemotherapeutic agents (13,21,22). In line with these findings, we have also reported that this gene is up-regulated in a microarray analysis of glioblastoma cells treated with the metabolically active anticancer compound fenofibrate (4).…”

Regulation of the JMJD3 (KDM6B) histone demethylase in glioblastoma stem cells by STAT3

“…These genes are known to play roles in neural development [51, 52]. GDF15 has also been shown to induce apoptosis and inhibit tumorigenesis in GBM [53, 54]. …”

E11/Podoplanin Protein Stabilization Through Inhibition of the Proteasome Promotes Osteocyte Differentiation in Murine in Vitro Models

“…As well as the observed increase in E11 protein expression, we also revealed that Bortezomib/ALLN/MG132 increased E11 mRNA levels. In other studies MG132 and Bortezomib have been reported to induce mRNA increases through both transcriptional (promoter activation) and post‐transcriptional (mRNA stability) mechanisms (Butler et al, ; Laroia et al, ; Shimizu et al, ). Conversely, MG132 causes defective polyadenylation (Lee and Moore, ) and whilst it has been previously shown that in human tissues, there is a 2.7 kb and a 0.9 kb E11 mRNA species, which differ in their polyadenylation (Martin‐Villar et al, ), there is no suggestion that this is the case in murine tissues.…”