title: 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.
authors.affiliation: Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Sachie
authors.initials: S
authors.lastname: Shimizu
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Kadowaki
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yoshioka
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kambe
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.forename: H Karimi
authors.initials: HK
authors.lastname: Kinyamu
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Eling
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D005909:Glioblastoma / Q000378:metabolism*; D055436:Growth Differentiation Factor 15 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology*; D051379:Mice; D011401:Promoter Regions, Genetic / Q000187:drug effects; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D015853:Cysteine Proteinase Inhibitors; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D007976:Leupeptins; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; D048051:p38 Mitogen-Activated Protein Kinases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde