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Wild-type IDH2 is a therapeutic target for triple-negative breast cancer

Author

Listed:
  • Jiang-jiang Li

    (Sun Yat-sen University Cancer Center)

  • Tiantian Yu

    (Sun Yat-sen University Zhongshan School of Medicine)

  • Peiting Zeng

    (Sun Yat-sen University Cancer Center)

  • Jingyu Tian

    (Sun Yat-sen University Cancer Center)

  • Panpan Liu

    (Sun Yat-sen University Cancer Center
    Sun Yat-sen University Cancer Center)

  • Shuang Qiao

    (Sun Yat-sen University Cancer Center)

  • Shijun Wen

    (Sun Yat-sen University Cancer Center)

  • Yumin Hu

    (Sun Yat-sen University Cancer Center)

  • Qiao Liu

    (Sun Yat-sen University Cancer Center)

  • Wenhua Lu

    (Sun Yat-sen University Cancer Center)

  • Hui Zhang

    (Sun Yat-sen University Cancer Center
    Sun Yat-sen University Zhongshan School of Medicine)

  • Peng Huang

    (Sun Yat-sen University Cancer Center
    Sun Yat-sen University Zhongshan School of Medicine)

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.

Suggested Citation

  • Jiang-jiang Li & Tiantian Yu & Peiting Zeng & Jingyu Tian & Panpan Liu & Shuang Qiao & Shijun Wen & Yumin Hu & Qiao Liu & Wenhua Lu & Hui Zhang & Peng Huang, 2024. "Wild-type IDH2 is a therapeutic target for triple-negative breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47536-6
    DOI: 10.1038/s41467-024-47536-6
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