IDH1 Mutation Promotes Tumorigenesis by Inhibiting JNK Activation and Apoptosis Induced by Serum Starvation
Open accessAbstract
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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The emerging role of Krebs cycle intermediates opens the possibility of manipulating levels and impacts of mitochondrial metabolites within the matrix, the rest of the cell, or after release into circulation.
“the emerging role of Krebs cycle intermediates in many central biomedical pathways opens up the possibility of extending mitochondrial pharmacology164-167 to manipulating the levels and impacts of mitochondrial metabolites both within the matrix, the rest of the cell, or following their release from the cell into the circulation.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [165]
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References 37 · Cited by 33
- Authors
- Jiang, B., Zhang, J., Xia, J., Zhao, W., Wu, Y., Shi, M., Luo, L., Zhou, H., Chen, A., Ma, H., Zhao, Q., Suleman, M., Lin, F., Zhou, L., Wang, J., Zhang, Y., He, Y., Li, X., Hung, L.-M., Mak, T. W., & Li, Q.
- Affiliations
- Xiamen University (CN)
- Tianjin Huanhu Hospital (CN)
- Xiamen Medical College (CN)
- Chang Gung University (TW)
- University Health Network (CA)
- Corresponding author
- Li, Qinxi
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 19
- Issue
- 2
- Pages
- 389-400
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2607321425
- Cited by
- 33
- References
- 37
- Citations by year
- 2026: 5 · 2025: 1 · 2024: 5 · 2023: 5 · 2022: 1 · 2021: 5 · 2020: 1 · 2019: 3 · 2018: 5 · 2017: 2
- FWCI
- 1.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Natural Science Foundation of China (81372702, 81402285, 31571473)
- Fundamental Research Funds for the Central Universities (20720140552, 10120100002)
- Specialized Research Fund for the Doctoral Program of Higher Education of China (20120121110005)
- National Science Foundation of China for Fostering Talents in Basic Research (J1310027)
- 111 Project of Education of China (B06016)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- IDH1 mutation, 2-hydroxyglutarate, JNK activation, Cdc42, MLK3, building information modeling, carcinogenesis, IDH1 R132H mutation, glioma, apoptosis resistance
- MeSH terms
- Animals, Glioma, Glutarates, Humans, Isocitrate Dehydrogenase, Gene Expression Regulation, Neoplastic, Culture Media, Serum-Free, Apoptosis, MAP Kinase Signaling System, Xenograft Model Antitumor Assays, Cell Line, Tumor, MAP Kinase Kinase 4, Mice, Carcinogenesis
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