IDH1 Mutation Promotes Tumorigenesis by Inhibiting JNK Activation and Apoptosis Induced by Serum Starvation

Publication date: 11 April 2017
Source:Cell Reports, Volume 19, Issue 2
Author(s): Bin Jiang, Jia Zhang, Jinmei Xia, Wentao Zhao, Yanan Wu, Minggang Shi, Lianzhong Luo, Huamin Zhou, Ai Chen, Huanhuan Ma, Qingwen Zhao, Muhammad Suleman, Furong Lin, Lin Zhou, Jinyang Wang, Yan Zhang, Ying He, Xiaotong Li, Li-Man Hung, Tak Wah Mak, Qinxi Li
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.

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Teaser

Jiang et al. report that oncometabolite 2-HG, produced by tumor-associated IDH1 mutation, physically binds to Cdc42 and abolishes its association with MLK3 and consequently disrupts JNK activation and apoptosis induced by serum deprivation. Loss of JNK-mediated apoptosis may be a key event in tumorigenesis driven by 2-HG.


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