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首页> 外文期刊>Biochimica et biophysica acta. Molecular basis of disease: BBA >The metastasis suppressor, NDRG1, differentially modulates the endoplasmic reticulum stress response
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The metastasis suppressor, NDRG1, differentially modulates the endoplasmic reticulum stress response

机译：转移抑制剂NDRG1，差异地调节内质网应力响应

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摘要

The metastasis suppressor, N-myc downstream regulated gene-1 (NDRG1), is a stress response protein that is involved in the inhibition of multiple oncogenic signaling pathways. Initial studies have linked NDRG1 and the endoplasmic reticulum (ER) stress response. Considering this, we extensively examined the mechanism by which NDRG1 regulates the ER stress response in pancreatic and colon cancer cells. We also examined the anti-cancer agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), which induces NDRG1 expression and causes ER stress. The expression of NDRG1 was demonstrated to regulate the three main arms of the ER stress response by: (1) increasing the expression of three major ER chaperones, binding immunoglobulin protein (BiP), calreticulin, and calnexin; (2) suppressing the protein kinase, RNA-activated (PKR)-like ER kinase (PERK); (3) inhibiting the inositol-requiring kinase 1 alpha (IRE1 alpha) arm; and (4) increasing the cleavage of activating transcription factor 6 (ATF6). An important finding was that NDRG1 enhances the anti-proliferative and anti-migratory activity of Dp44mT. This increased efficacy could be related to the following effects in the presence of Dp44mT and NDRG1, namely: markedly increased activation of the PERK target, eukaryotic translation initiation factor 2 alpha (eIF2 alpha); the maintenance of activating transcription factor 4 (ATF4) expression; high cytosolic Ca+2 that increases the sensitivity of cells to apoptosis via activation of the calmodulin-dependent kinase II (CaMKII) signaling cascade; and increased pro-apoptotic C/EBP-homologous protein (CHOP) expression. Collectively, this investigation dissects the molecular mechanisms through which NDRG1 manipulates the ER stress response and its ability to potentiate the activity of the potent anti-cancer agent, Dp44mT.
机译：转移抑制剂N-MYC下游调节基因-1（NDRG1）是应力应答蛋白，其参与抑制多种致癌信号传导途径。初始研究具有连接的NDRG1和内质网（ER）应激反应。考虑到这一点，我们广泛地检查了NDRG1调节胰腺和结肠癌细胞中ER应激反应的机制。我们还研究了抗癌剂，二-2-吡啶基4,4-二甲基-3-硫代吡啶吩（DP44MT），其诱导NDRG1表达并引起ER应力。对NDRG1的表明表明，调节ER应激响应的三个主要臂：（1）增加三个主要ER伴侣的表达，结合免疫球蛋白蛋白（BIP），Caltreticulin和Calnexin; （2）抑制蛋白激酶，RNA活化（PKR） - 样ER激酶（PERK）; （3）抑制需要肌醇的激酶1α（IS1α）臂; （4）增加激活转录因子6的切割（ATF6）。重要的发现是NDRG1增强了DP44MT的抗增殖和抗迁移活性。这种增加的疗效可能与DP44MT和NDRG1存在下的以下效果有关，即：显着增加了PERK靶的激活，真核翻译引发因子2α（EIF2 alpha）;活化转录因子4（ATF4）表达的维持;高细胞溶溶胶Ca + 2通过激活钙调蛋白依赖性激酶II（Camkii）信号级联的激活增加细胞对细胞凋亡的敏感性;并增加促凋亡C / EBP-同源蛋白（Chec）表达。统称，这项调查描述了NDRG1操纵ER应激反应的分子机制及其使有效抗癌剂，DP44MT活性的能力。

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