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Wild-type IDH2 is a therapeutic target for triple-negative breast cancer
Jiang-Jiang Li1, Tiantian Yu2, Peiting Zeng1
1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, China.
Abstract:
Mutations in isocitrate dehydrogenases (IDH) are oncogenic events due to the generation of oncogenic metabolite 2-hydroxyglutarate. However, the role of wild-type IDH in cancer development remains elusive. Here we show that wild-type IDH2 is highly expressed in triple negative breast cancer (TNBC) cells and promotes their proliferation in vitro and tumor growth in vivo. Genetic silencing or pharmacological inhibition of wt-IDH2 causes a significant increase in α-ketoglutarate (α-KG), indicating a suppression of reductive tricarboxylic acid (TCA) cycle. The aberrant accumulation of α-KG due to IDH2 abrogation inhibits mitochondrial ATP synthesis and promotes HIF-1α degradation, leading to suppression of glycolysis. Such metabolic double-hit results in ATP depletion and suppression of tumor growth, and renders TNBC cells more sensitive to doxorubicin treatment. Our study reveals a metabolic property of TNBC cells with active utilization of glutamine via reductive TCA metabolism, and suggests that wild-type IDH2 plays an important role in this metabolic process and could be a potential therapeutic target for TNBC.
Insights
Wild-type IDH2 promotes triple-negative breast cancer (TNBC) growth by fueling reductive metabolism. Inhibiting wild-type IDH2 depletes ATP, suppresses tumor growth, and enhances doxorubicin sensitivity.
Area of Science:
- Metabolic pathways in oncology
- Cancer cell metabolism
- Biochemical mechanisms of cancer progression
Background:
- Mutant isocitrate dehydrogenases (IDH) generate 2-hydroxyglutarate, driving oncogenesis.
- The role of wild-type IDH in cancer, particularly triple-negative breast cancer (TNBC), is not well understood.
Purpose of the Study:
- To investigate the role of wild-type IDH2 in TNBC proliferation and tumor growth.
- To elucidate the metabolic consequences of wild-type IDH2 activity in TNBC.
- To explore wild-type IDH2 as a potential therapeutic target for TNBC.
Main Methods:
- Assessed wild-type IDH2 expression in TNBC cells.
- Utilized genetic silencing and pharmacological inhibition of wild-type IDH2.
- Measured α-ketoglutarate (α-KG) levels and TCA cycle activity.
- Analyzed mitochondrial ATP synthesis, glycolysis, and HIF-1α levels.
- Evaluated tumor growth in vivo and sensitivity to doxorubicin.
Main Results:
- Wild-type IDH2 is highly expressed in TNBC and promotes proliferation and tumor growth.
- Inhibition of wild-type IDH2 increases α-KG, suppresses the reductive TCA cycle, and depletes ATP.
- Reduced ATP and HIF-1α degradation lead to suppressed glycolysis.
- TNBC cells with inhibited wild-type IDH2 show increased sensitivity to doxorubicin.
Conclusions:
- TNBC cells utilize glutamine via reductive TCA metabolism, dependent on wild-type IDH2.
- Wild-type IDH2 is crucial for TNBC metabolic adaptation and growth.
- Targeting wild-type IDH2 represents a promising therapeutic strategy for TNBC.
