Jiang Bin, Zhang Jia, Xia Jinmei, Zhao Wentao, Wu Yanan, Shi Minggang, Luo Lianzhong, Zhou Huamin, Chen Ai, Ma Huanhuan, Zhao Qingwen, Suleman Muhammad, Lin Furong, Zhou Lin, Wang Jinyang, Zhang Yan, He Ying, Li Xiaotong, Hung Li-Man, Mak Tak Wah, Li Qinxi
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
Key Laboratory of Marine Biogenetic Resources, Third Institute of Oceanography, State Oceanic Administration, Xiamen 361005, China.
Cell Rep. 2017 Apr 11;19(2):389-400. doi: 10.1016/j.celrep.2017.03.053.
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.
癌细胞的两个标志是它们对细胞凋亡的抗性以及在重要血清成分水平降低的情况下仍能旺盛生长的能力。c-Jun氨基末端激酶（JNK）的激活对于血清饥饿（SS）引发的细胞凋亡至关重要，而异柠檬酸脱氢酶1（IDH1）突变具有致瘤性，部分原因是它们产生异常代谢物2-羟基戊二酸（2-HG）。然而，尚不清楚2-HG诱导的肿瘤发生是否部分归因于JNK抑制，从而导致SS诱导的细胞凋亡存在缺陷。我们在此使用IDH1-R132Q敲入突变小鼠细胞表明，2-HG仅抑制由SS诱导而非紫外线或阿霉素诱导的JNK激活，因此可阻断细胞凋亡。在血清饥饿时，Cdc42通常会破坏混合谱系激酶3（MLK3）的自抑制，触发MLK3-MKK4/7-JNK-Bim凋亡级联反应。2-HG与Cdc42结合并消除其与MLK3的结合，使MLK3失活并导致细胞凋亡。小鼠体内移植瘤实验表明，这一机制有助于突变型IDH1驱动肿瘤发生，这一结果在携带IDH1-R132H突变的人类胶质瘤中检测到JNK失活得到了证实。
