Proteasome inhibitor MG132 induces NAG-1/GDF15 expression through the p38 MAPK pathway in glioblastoma cells.
Proteasome inhibitor MG132 induces NAG-1/GDF15 expression through the p38 MAPK pathway in glioblastoma cells.
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DOI：
10.1016/j.bbrc.2012.11.137
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发表时间：
2013-01-25
影响因子：
3.1
通讯作者：
Eling, Thomas E.
中科院分区：
文献类型：
--
作者：
Shimizu, Sachie;Kadowaki, Mitsutoshi;Yoshioka, Hiroki;Kambe, Atsushi;Watanabe, Takashi;Kinyamu, H. Karimi;Eling, Thomas E.
非甾体抗炎药激活基因1 （NAG-1）的表达受p53和Egr-1肿瘤抑制通路的调控。许多抗癌药物和化学物质诱导NAG-1表达，但其机制尚不完全清楚。表达人类NAG-1的转基因小鼠对肠道和前列腺癌具有抗性，表明NAG-1是一种肿瘤抑制因子。蛋白酶体抑制剂在临床前研究中表现出抗胶质母细胞瘤的活性。本研究表明，蛋白酶体抑制剂MG132和硼替佐米可诱导成胶质细胞瘤细胞中NAG-1的表达和分泌。MG132通过转录和转录后机制增加NAG-1的表达。在转录水平上，NAG-1的诱导需要启动子的−133到+41 bp区域。在转录后水平，MG132通过将na -1 mRNA的半衰期从1.5 h增加到80 h来稳定na -1 mRNA。由于mRNA稳定性的显著增加，这可能是MG132介导的na -1诱导的主要原因。对其机制的进一步研究表明，MG132增加了p38 MAPK通路的磷酸化。因此，抑制p38磷酸化阻断了NAG-1启动子的激活并降低了mRNA的稳定性，这表明p38 MAPK激活既介导了mg132依赖性启动子的激活，也介导了NAG-1 mRNA的稳定。我们提出p38 MAPK诱导NAG-1是蛋白酶体抑制剂抗胶质母细胞瘤活性的潜在贡献者。
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.
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影响因子：
8
作者：
Albertoni, M;Shaw, PH;Hegi, ME
通讯作者：
Hegi, ME
影响因子：
11.2
作者：
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通讯作者：
Bhaumik, Sukesh R.
影响因子：
4.8
作者：
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通讯作者：
Eling, TE
影响因子：
8
作者：
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通讯作者：
Koeffler, HP
影响因子：
29.4
作者：
Baek, Seung Joon;Okazaki, Ryuji;Eling, Thomas E.
通讯作者：
Eling, Thomas E.