Abstract:
: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.
journal_name
Cell Repjournal_title
Cell reportsauthors
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 LM,Mak TW,Li Qdoi
10.1016/j.celrep.2017.03.053subject
Has Abstractpub_date
2017-04-11 00:00:00pages
389-400issue
2issn
2211-1247pii
S2211-1247(17)30399-6journal_volume
19pub_type
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