IDH1 Mutation Promotes Tumorigenesis by Inhibiting JNK Activation and Apoptosis Induced by Serum Starvation
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
Affiliations
Bin Jiang
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Jia Zhang
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Jinmei Xia
Key Laboratory of Marine Biogenetic Resources, Third Institute of Oceanography, State Oceanic Administration, Xiamen 361005, China
Wentao Zhao
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Yanan Wu
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Minggang Shi
Department of Neurosurgery, Huanhu Hospital, No. 6 Jizhao Road, Jinnan District, Tianjin, 30050, China
Lianzhong Luo
Xiamen Key Laboratory of Marine Medicinal Natural Products and Cell Engineering, Xiamen Medical College, Xiamen 361008, China
Huamin Zhou
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Ai Chen
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Huanhuan Ma
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Qingwen Zhao
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Muhammad Suleman
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Furong Lin
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Lin Zhou
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Jinyang Wang
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Yan Zhang
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Ying He
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Xiaotong Li
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Li-Man Hung
Department and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Tao-Yuan 33302, Taiwan
Tak Wah Mak
The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2C1, Canada
Qinxi Li
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2C1, Canada; Corresponding author
Summary: 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. : 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. Keywords: IDHI R123 mutation, serum starvation, JNK, MLK3, apoptosis, 2-HG, tumorigenesis
