IDH1 Mutation Promotes Tumorigenesis by Inhibiting JNK Activation and Apoptosis Induced by Serum Starvation
IDH1 Mutation Promotes Tumorigenesis by Inhibiting JNK Activation and Apoptosis Induced by Serum Starvation
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IDH1 突变通过抑制血清饥饿诱导的 JNK 激活和细胞凋亡促进肿瘤发生
DOI：
10.1016/j.celrep.2017.03.053
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发表时间：
2017-04-11
期刊：
影响因子：
8.8
通讯作者：
Li, Qinxi
中科院分区：
文献类型：
--
作者：
Jiang, Bin;Zhang, Jia;Li, Qinxi
癌细胞的两个标志是它们对细胞凋亡的抵抗力以及尽管重要血清成分水平降低但仍能茁壮成长的能力。c-jun N-末端激酶（JNK）激活对于由血清饥饿（SS）触发的细胞凋亡是至关重要的，并且异柠檬酸脱氢酶1（IDH 1）突变是致瘤的，部分原因是它们产生异常代谢物2-羟基戊二酸（2-HG）。然而，目前尚不清楚2-HG诱导的肿瘤发生是否部分是由于JNK抑制，从而有缺陷的SS诱导的细胞凋亡。在这里，我们表明，使用IDH 1-R132 Q敲入突变小鼠细胞，2-HG抑制JNK激活诱导的SS，而不是由UV或阿霉素，因此可以阻止细胞凋亡。在SS时，Cdc 42通常破坏混合谱系激酶3（MLK 3）的自抑制，触发MLK 3-MKK 4/7-JNK-Bim凋亡级联。2-HG与Cdc 42结合并消除其与MLK 3的结合，使MLK 3失活和凋亡。小鼠中的同种异体移植肿瘤测定表明，这种机制有助于由突变IDH 1驱动的肿瘤发生，这一结果通过检测携带IDH 1-R132 H突变的人胶质瘤中的JNK失活得到证实。
Two hallmarks of cancer cells are their resistance to apoptosis and ability to thrive despite reduced levels of vital serum components. c-jun N-terminal kinase (JNK) activation is crucial for apoptosis triggered by serum starvation (SS), and isocitrate dehydrogenase 1 (IDH1) mutations are tumorigenic, in part, because they produce the abnormal metabolite 2-hydroxyglutarate (2-HG). However, it is unknown whether 2-HG-induced tumorigenesis is partially due to JNK inhibition and thus defective SS-induced apoptosis. We show here, using IDH1-R132Q knockin mutant mouse cells, that 2-HG inhibits JNK activation induced only by SS and not by UV or doxorubicin, and thus can block apoptosis. Upon SS, Cdc42 normally disrupts mixed lineage kinase 3's (MLK3's) auto-inhibition, triggering the MLK3-MKK4/7-JNK-Bim apoptotic cascade. 2-HG binds to Cdc42 and abolishes its association with MLK3, inactivating MLK3 and apoptosis. Allograft tumor assays in mice demonstrate that this mechanism contributes to tumorigenesis driven by mutant IDH1, a result confirmed by detection of JNK inactivation in human gliomas harboring IDH1-R132H mutations.