Inhibition of eIF2α dephosphorylation enhances TRAIL-induced apoptosis in hepatoma cells.
Inhibition of eIF2α dephosphorylation enhances TRAIL-induced apoptosis in hepatoma cells.
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抑制 eIF2α 去磷酸化增强 TRAIL 诱导的肝癌细胞凋亡
DOI：
10.1038/cddis.2014.24
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发表时间：
2014-02-13
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
肿瘤坏死因子相关凋亡诱导配体（TRAIL）是一种肿瘤细胞死亡诱导剂，在癌症治疗中有希望。癌细胞比正常细胞更容易受到TRAIL的细胞死亡诱导作用的影响。然而，多种癌细胞通过复杂的机制对TRAIL产生抗性。在此，我们研究了抑制真核起始因子2亚基α（eIF 2 α）去磷酸化对TRAIL诱导的肝癌细胞凋亡的影响。用salubrinal（eIF 2 α去磷酸化抑制剂）处理肝癌细胞，可增强TRAIL诱导的eIF 2 α磷酸化、CCAAT/增强子结合蛋白同源蛋白（CHOP）表达和caspase活化。Salubrinal增强TRAIL诱导的细胞凋亡，这可以被半胱天冬酶抑制剂消除。磷酸模拟物eIF 2 α（S51 D）的过表达增强了TRAIL诱导的CHOP表达、半胱氨酸蛋白酶7和PARP切割和细胞凋亡。相比之下，磷酸缺陷型eIF 2 α（S51 A）的过表达消除了salubrinal对TRAIL诱导的细胞凋亡的刺激。此外，生长停滞和DNA损伤诱导蛋白34（GADD 34）的敲低（其募集蛋白磷酸酶1以使eIF 2 α去磷酸化）增强TRAIL诱导的eIF 2 α磷酸化、CHOP表达、半胱天冬酶激活和凋亡。此外，salubrinal对肝癌细胞对TRAIL的增敏依赖于CHOP。敲低CHOP消除salubrinal对TRAIL诱导的caspase活化和凋亡的刺激。salubrinal和TRAIL的组合导致Bim（一种CHOP调节的促凋亡蛋白）的表达增加。Bim敲低减弱salubrinal对TRAIL诱导的细胞凋亡的刺激作用。总的来说，这些发现表明抑制eIF 2 α去磷酸化可能导致TRAIL处理的肝癌细胞的合成致死性。
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an inducer of cancer cell death that holds promise in cancer therapy. Cancer cells are more susceptible than normal cells to the cell-death-inducing effects of TRAIL. However, a variety of cancer cells are resistant to TRAIL through complex mechanisms. Here, we investigate the effects of inhibition of eukaryotic initiation factor 2 subunit α (eIF2α) dephosphorylation on TRAIL-induced apoptosis in hepatoma cells. Treatment of hepatoma cells with salubrinal, an inhibitor of eIF2α dephosphorylation, enhances TRAIL-induced eIF2α phosphorylation, CCAAT/enhancer-binding protein homologous protein (CHOP) expression and caspase activation. Salubrinal enhances TRAIL-induced apoptosis, which could be abrogated by caspase inhibitor. Overexpression of phosphomimetic eIF2α (S51D) enhances TRAIL-induced CHOP expression, caspase 7 and PARP cleavage and apoptosis. By contrast, overexpression of phosphodeficient eIF2α (S51A) abrogates the stimulation of TRAIL-induced apoptosis by salubrinal. Moreover, knockdown of growth arrest and DNA damage-inducible protein 34 (GADD34), which recruits protein phosphatase 1 to dephosphorylate eIF2α, enhances TRAIL-induced eIF2α phosphorylation, CHOP expression, caspase activation and apoptosis. Furthermore, the sensitization of hepatoma cells to TRAIL by salubrinal is dependent on CHOP. Knockdown of CHOP abrogates the stimulation of TRAIL-induced caspase activation and apoptosis by salubrinal. Combination of salubrinal and TRAIL leads to increased expression of Bim, a CHOP-regulated proapoptotic protein. Bim knockdown blunts the stimulatory effect of salubrinal on TRAIL-induced apoptosis. Collectively, these findings suggest that inhibition of eIF2α dephosphorylation may lead to synthetic lethality in TRAIL-treated hepatoma cells.
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影响因子：
16
作者：
Harding, HP;Zhang, YH;Ron, D
通讯作者：
Ron, D
影响因子：
4.8
作者：
Cnop, Miriam;Ladriere, Laurence;Eizirik, Decio L.
通讯作者：
Eizirik, Decio L.
影响因子：
9.2
作者：
Deng, J;Harding, HP;Sonenberg, N
通讯作者：
Sonenberg, N
DOI：
10.1083/jcb.153.5.1011
发表时间：
2001-05-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Novoa I;Zeng H;Harding HP;Ron D
通讯作者：
Ron D
影响因子：
4.1
作者：
Jiang, HY;Wek, RC
通讯作者：
Wek, RC