IDH2 compensates for IDH1 mutation to maintain cell survival under hypoxic conditions in IDH1‑mutant tumor cells.

Mutations of isocitrate dehydrogenase (IDH) 1 and 2 occur in low-grade gliomas, acute myeloid leukemias and other types of solid cancer. By catalyzing the reversible conversion between isocitrate and alpha-ketoglutarate (alpha-KG), IDH1 and 2 contribute to the central process of metabolism, including oxidative and reductive metabolism. IDH1 and 2 mutations result in the loss of normal catalytic function and acquire neomorphic activity, facilitating the conversion of alpha-KG into an oncometabolite, (R)-2-hydroxyglutarate, which can cause epigenetic modifications and tumorigenesis. Small-molecule inhibitors of mutant IDH1 and 2 have been developed, and ongoing clinical trials have shown promising results in hematological malignancies, but not in gliomas. These previous findings make it necessary to identify the mechanism and develop more effective therapies for IDH1-mutant gliomas. In the present study, it was demonstrated that under hypoxic conditions, patient-derived primary glioma cells and HCT116 cells, both of which carry a monoallelic IDH1 arginine 132 to histidine mutation (R132H), have a slower growth rate than the corresponding wild-type IDH1 cells. Western blot analysis showed that IDH1 R132H-mutant cancer cells exhibited upregulated IDH2 protein expression under hypoxic conditions. Furthermore, the silencing of IDH2 using small interfering RNA significantly inhibited the growth of IDH1-mutant cells under hypoxic conditions. Finally, [U-C-13(5)]glutamine tracer analysis showed that IDH2 knockdown reduced the reductive carboxylation of alpha-KG into isocitrate in HCT116(R132H/+) cells under hypoxic conditions. The present study showed for the first time, to the best of our knowledge, that IDH2 plays a compensatory role in maintaining reductive carboxylation-dependent lipogenesis and proliferation in IDH1 R132H tumor cells. Therefore, IDH2 could serve as a potential anti-tumor target for IDH1-mutant tumors, which may provide a new strategy for treatment.