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.
Glioblastoma multiforme (GBM) is the highly invasive primary tumors with a poor prognosis despite current surgical, radiation and chemotherapy approaches. Proteasome inhibitor, an approved drug for treatment of hematological cancer is currently being tested in clinical trials against various malignancies, including GBM. The pro-apoptotic and antitumorigenic protein NAG-1(nonsteroidal anti-inflammatory drug-activated gene-1) is a divergent member of the transforming growth factor-beta (TGF-beta) superfamily. We showed that the proteasome inhibitor, MG132 induces NAG-1 protein and mRNA expression and apoptosis in a concentration-dependent manner in U87 cells. Studies with NAG-1 luciferase reporter constructs show that the −133 to +41 region of the NAG-1 promoter is activated by MG132 however activation does not require the Sp-/Egr-1 binding site. Using the selective pharmacologic p38 mitogen -activated protein kinase (MAPK) inhibitor, we showed that NAG-1 induction following MG132 is mediated by the p38 MAPK pathway. Pretreatment with MAPK inhibitor, SB203580 and SB202190, blocked the MG132-induced NAG-1 expression, whereas an inhibition of p53, JUNK, MEK, PKC, PKA activity had no effect on NAG-1 levels. In summary, our data indicate linkage between p38MAPK, NAG-1 and the proteasome inhibitor, MG132 and provides a new clue to the molecular mechanism of the antitumorigenic activity of NAG-1.
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