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SLC13A3 is a major effector downstream of activated β-catenin in liver cancer pathogenesis

Author

Listed:
  • Wennan Zhao

    (Tianjin University)

  • Xue Wang

    (University of California Berkeley
    University of Hawaii Cancer Center)

  • Lifeng Han

    (Tianjin University of Traditional Chinese Medicine)

  • Chunze Zhang

    (Tianjin Union Medical Center)

  • Chenxi Wang

    (Tianjin University of Traditional Chinese Medicine)

  • Dexin Kong

    (Tianjin Medical University)

  • Mingzhe Zhang

    (Tianjin University)

  • Tong Xu

    (Tianjin University)

  • Gen Li

    (Tianjin University)

  • Ge Hu

    (Tianjin University)

  • Jiahua Luo

    (Tianjin University)

  • Sook Wah Yee

    (University of California)

  • Jia Yang

    (University of California)

  • Andreas Stahl

    (University of California Berkeley)

  • Xin Chen

    (University of Hawaii Cancer Center
    University of California)

  • Youcai Zhang

    (Tianjin University)

Abstract

Activated Wnt/β-catenin pathway is a key genetic event in liver cancer development. Solute carrier (SLC) transporters are promising drug targets. Here, we identify SLC13A3 as a drug-targetable effector downstream of β-catenin in liver cancer. SLC13A3 expression is elevated in human liver cancer samples with gain of function (GOF) mutant CTNNB1, the gene encoding β-catenin. Activation of β-catenin up-regulates SLC13A3, leading to intracellular accumulation of endogenous SLC13A3 substrates. SLC13A3 is identified as a low-affinity transporter for glutathione (GSH). Silencing of SLC13A3 downregulates the leucine transporter SLC7A5 via c-MYC signaling, leading to leucine depletion and mTOR inactivation. Furthermore, silencing of SLC13A3 depletes GSH and induces autophagic ferroptosis in β-catenin-activated liver cancer cells. Importantly, both genetic inhibition of SLC13A3 and a small molecule SLC13A3 inhibitor suppress β-catenin-driven hepatocarcinogenesis in mice. Altogether, our study suggests that SLC13A3 could be a promising therapeutic target for treating human liver cancers with GOF CTNNB1 mutations.

Suggested Citation

  • Wennan Zhao & Xue Wang & Lifeng Han & Chunze Zhang & Chenxi Wang & Dexin Kong & Mingzhe Zhang & Tong Xu & Gen Li & Ge Hu & Jiahua Luo & Sook Wah Yee & Jia Yang & Andreas Stahl & Xin Chen & Youcai Zhan, 2024. "SLC13A3 is a major effector downstream of activated β-catenin in liver cancer pathogenesis," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51860-2
    DOI: 10.1038/s41467-024-51860-2
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    References listed on IDEAS

    as
    1. Inmaculada Martínez-Reyes & Navdeep S. Chandel, 2020. "Mitochondrial TCA cycle metabolites control physiology and disease," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    2. Jie Chen & Yuhui Ou & Rong Luo & Jie Wang & Dong Wang & Jialiang Guan & Yi Li & Peixue Xia & Peng R. Chen & Ying Liu, 2021. "SAR1B senses leucine levels to regulate mTORC1 signalling," Nature, Nature, vol. 596(7871), pages 281-284, August.
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