Involvement of general control nonderepressible kinase 2 in cancer cell apoptosis by posttranslational mechanisms.
Involvement of general control nonderepressible kinase 2 in cancer cell apoptosis by posttranslational mechanisms.
复制标题
一般控制非阻抑性激酶 2 通过翻译后机制参与癌细胞凋亡。
DOI：
10.1091/mbc.e14-10-1438
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发表时间：
2015-03-15
影响因子：
3.3
通讯作者：
Wu Y
中科院分区：
文献类型：
--
作者：
Wei C;Lin M;Jinjun B;Su F;Dan C;Yan C;Jie Y;Jin Z;Zi-Chun H;Wu Y
GCN2通过翻译后机制在癌细胞死亡过程中发挥促凋亡作用。GCN2的表达调控可用于分子靶向肿瘤治疗和药物开发。Na+，K+-ATPase配体是最早被发现的能够通过调节GCN2信号而引发癌细胞死亡的小分子药物。一般控制的不可降压蛋白2(GCN2)是一种很有前途的肿瘤治疗靶点。然而，GCN2在癌细胞存活或死亡中的作用尚不清楚；此外，靶向GCN2信号的小分子也不可用。通过基于GCN2水平的药物筛选实验，我们发现GCN2蛋白水平在体外和体内都决定了癌细胞对Na+，K+-ATPase配体诱导的凋亡的敏感性，这种作用在很大程度上依赖于C/EBP同源蛋白(CHOP)的诱导。进一步分析表明，GCN2是一种短命蛋白质。在A549肺癌细胞中，β-arrestin1/2与GCN2结合，并通过重新启动E3连接酶NEDD4L，促进随后的蛋白酶体降解，将GCN2蛋白水平维持在较低水平。然而，Na+，K+-ATPase配体处理触发了GCN2在苏氨酸899位的磷酸化，这通过破坏GCN2-β-Arrestin-NEDD4L三元复合体的形成而增加了GCN2的蛋白水平。GCN2水平的升高反过来加重了Na+，K+-ATPase配体诱导的癌细胞凋亡。我们的研究结果表明，GCN2可以通过翻译后机制在癌细胞死亡中发挥其促凋亡作用。此外，Na+，K+-ATPase配体作为第一种被发现的小分子药物，可以通过调节GCN2信号来引发癌细胞死亡。
GCN2 exerts its proapoptotic function in cancer cell death by posttranslational mechanisms. Modulation of GCN2 expression can be used for molecular targeted cancer therapy and drug development. Na+,K+-ATPase ligands are the first identified small-molecule drugs that can trigger cancer cell death by modulating GCN2 signaling. General control nonderepressible kinase 2 (GCN2) is a promising target for cancer therapy. However, the role of GCN2 in cancer cell survival or death is elusive; further, small molecules targeting GCN2 signaling are not available. By using a GCN2 level-based drug screening assay, we found that GCN2 protein level critically determined the sensitivity of the cancer cells toward Na+,K+-ATPase ligand–induced apoptosis both in vitro and in vivo, and this effect was largely dependent on C/EBP homologous protein (CHOP) induction. Further analysis revealed that GCN2 is a short-lived protein. In A549 lung carcinoma cells, cellular β-arrestin1/2 associated with GCN2 and maintained the GCN2 protein level at a low level by recruiting the E3 ligase NEDD4L and facilitating consequent proteasomal degradation. However, Na+,K+-ATPase ligand treatment triggered the phosphorylation of GCN2 at threonine 899, which increased the GCN2 protein level by disrupting the formation of GCN2–β-arrestin–NEDD4L ternary complex. The enhanced GCN2 level, in turn, aggravated Na+,K+-ATPase ligand–induced cancer cell apoptosis. Our findings reveal that GCN2 can exert its proapoptotic function in cancer cell death by posttranslational mechanisms. Moreover, Na+,K+-ATPase ligands emerge as the first identified small-molecule drugs that can trigger cancer cell death by modulating GCN2 signaling.