Integrated regulation of autophagy and apoptosis by EEF2K controls cellular fate and modulates the efficacy of curcumin and velcade against tumor cells
Integrated regulation of autophagy and apoptosis by EEF2K controls cellular fate and modulates the efficacy of curcumin and velcade against tumor cells
复制标题
EEF2K 对自噬和细胞凋亡的综合调控控制细胞命运并调节姜黄素和万卡迪对抗肿瘤细胞的功效
DOI：
10.4161/auto.22801
复制
发表时间：
2013-02-01
期刊：
影响因子：
13.3
通讯作者：
Yang, Jin-Ming
中科院分区：
文献类型：
--
作者：
Cheng, Yan;Ren, Xingcong;Yang, Jin-Ming
内质网（ER）应激诱导自噬和细胞凋亡，但在经历ER应激的细胞中调节这两个细胞过程的分子机制和途径仍然不清楚。我们在这里报告，真核细胞延伸因子-2激酶（EEF 2K）是一个关键的控制器ER应激诱导的自噬和肿瘤细胞凋亡。DDIT 4是一种应激诱导蛋白，在内质网应激条件下，其参与了EEF 2K激活信号的转导。我们进一步表明，EEF 2K在Ser 398的磷酸化是诱导自噬所必需的，而激酶在Ser 366和Ser 78的磷酸化对自噬产生抑制作用。通过沉默EEF 2K抑制ER应激激活的自噬加重了ER应激并促进肿瘤细胞的凋亡性细胞死亡。此外，通过RNAi或NH 125（酶的小分子抑制剂）抑制EEF 2K使肿瘤细胞对姜黄素和万珂（具有ER应激诱导作用的两种抗癌剂）更敏感。我们的研究表明，DDIT 4-EEF 2K通路是诱导自噬和决定ER应激下肿瘤细胞的命运所必需的，并表明抑制EEF 2K介导的自噬可以恶化ER应激并导致更大的凋亡反应，从而增强ER应激诱导剂对癌症的功效。
Endoplasmic reticulum (ER) stress induces both autophagy and apoptosis yet the molecular mechanisms and pathways underlying the regulation of these two cellular processes in cells undergoing ER stress remain less clear. We report here that eukaryotic elongation factor-2 kinase (EEF2K) is a critical controller of the ER stress-induced autophagy and apoptosis in tumor cells. DDIT4, a stress-induced protein, was required for transducing the signal for activation of EEF2K under ER stress. We further showed that phosphorylation of EEF2K at Ser398 was essential for induction of autophagy, while phosphorylation of the kinase at Ser366 and Ser78 exerted an inhibitory effect on autophagy. Suppression of the ER stress-activated autophagy via silencing of EEF2K aggravated ER stress and promoted apoptotic cell death in tumor cells. Moreover, inhibiting EEF2K by either RNAi or NH125, a small molecule inhibitor of the enzyme, rendered tumor cells more sensitive to curcumin and velcade, two anticancer agents that possess ER stress-inducing action. Our study indicated that the DDIT4-EEF2K pathway was essential for inducing autophagy and for determining the fate of tumor cells under ER stress, and suggested that inhibiting the EEF2K-mediated autophagy can deteriorate ER stress and lead to a greater apoptotic response, thereby potentiating the efficacy of the ER stress-inducing agents against cancer.