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

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.

Targeting LncRNA-MALAT1 suppresses the progression of osteosarcoma by altering the expression and localization of β-catenin

“…Since the tumour microenvironment has an extremely low supply of serum components caused by the uncontrolled proliferation of malignant tumours, serum starvation can be used to simulate this barren microenvironment and thus observe the special mechanisms involved in the anti-apoptotic action of malignant tumours. 35 After 48 hours of serum starvation, a large proportion of MNNG/HOS cells were able to tolerate this barren simulated tumour microenvironment, while blocking the MALAT1/EZH2 axis could lead to maladjustment (Fig. 1 E).…”

“…The microenvironment of malignant tumours is extremely lacking in serum components, because of uncontrolled proliferation. 35 Hence, we used serum starvation to investigate the effect of this low-nutrient microenvironment on OS cells. We also found that siMALAT1 could promote cell apoptosis not only in the simulated environment in vitro but also in vivo .…”

Metabolism, Activity, and Targeting of D- and L-2-Hydroxyglutarates

“…D-2-HG was found to be able to competitively inhibit SDH resulting in the accumulation of succinate, increased protein hypersuccinylation, and impairment of mitochondrial respiration [ 100 ]. In addition, 2-HG has been reported to bind the DNA methyltransferase DNMT1 and the small GTPase Cdc42, although neither enzyme binds α-KG [ 101 , 102 ]. 2-HG stimulated DNMT1 to bind the promoter and repress the expression of receptor-interacting protein kinase 3 (RIP3), a regulator of programmed necrosis/necroptosis, suggesting that impaired RIP3-dependent necroptosis may contribute to tumorigenesis driven by IDH mutation [ 102 ].…”

“…2-HG stimulated DNMT1 to bind the promoter and repress the expression of receptor-interacting protein kinase 3 (RIP3), a regulator of programmed necrosis/necroptosis, suggesting that impaired RIP3-dependent necroptosis may contribute to tumorigenesis driven by IDH mutation [ 102 ]. Binding of 2-HG to Cdc42 disrupted Cdc42’s association with the effector mixed lineage kinase 3 (MLK3), leading to suppression of MLK3 activation and MLK3-mediated apoptosis in serum-deprived mutant IDH1 cells [ 101 ]. Future genetic and biophysical characterizations are necessary to understand the significance and affinities of 2-HG binding to DNMT1 and Cdc42.…”

EWSAT1 Acts in Concert with Exosomes in Osteosarcoma Progression and Tumor‐Induced Angiogenesis: The “Double Stacking Effect”

“…As the TME is characterized by both high metabolic rate and relatively low serum components due to abnormal proliferation, serum starvation is another frequently used method for evaluating the anti‐apoptotic activity and viability of malignant tumors. [ 5b,40 ]…”