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

Wennan Zhao1, Xue Wang2,3, Lifeng Han4

  • 1School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China.

Nature Communications
|August 30, 2024
PubMed

Insights

Researchers found that targeting the SLC13A3 transporter can suppress liver cancer growth driven by the Wnt/β-catenin pathway. Inhibiting SLC13A3 depletes glutathione and induces cell death in cancer cells.

Area of Science:

  • Hepatology
  • Molecular Oncology
  • Cancer Biology

Background:

  • The Wnt/β-catenin pathway is crucial in liver cancer development.
  • Solute carrier (SLC) transporters represent potential therapeutic targets in cancer treatment.

Purpose of the Study:

  • To identify and characterize SLC13A3 as a drug-targetable effector of the Wnt/β-catenin pathway in liver cancer.
  • To investigate the role of SLC13A3 in liver cancer cell metabolism and survival.

Main Methods:

  • Analysis of SLC13A3 expression in human liver cancer samples with CTNNB1 mutations.
  • Investigating the effect of β-catenin activation on SLC13A3 expression and function.
  • Assessing the impact of SLC13A3 silencing on glutathione (GSH) levels, leucine transport (SLC7A5), c-MYC, mTOR signaling, and ferroptosis.
  • Evaluating the efficacy of genetic and small molecule inhibition of SLC13A3 in mouse models of hepatocarcinogenesis.

Main Results:

  • SLC13A3 expression is upregulated in liver cancers with activating CTNNB1 mutations.
  • SLC13A3 transports glutathione (GSH) and its silencing leads to GSH depletion.
  • SLC13A3 inhibition downregulates SLC7A5 via c-MYC, causing leucine depletion and mTOR inactivation.
  • Silencing SLC13A3 induces autophagic ferroptosis in liver cancer cells.
  • Genetic and pharmacological inhibition of SLC13A3 suppresses tumor growth in vivo.

Conclusions:

  • SLC13A3 is a downstream effector of β-catenin in liver cancer.
  • Targeting SLC13A3 represents a promising therapeutic strategy for liver cancers with CTNNB1 gain-of-function mutations.

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