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

  • Nat Commun. 2024 Aug 30;15(1):7522. doi: 10.1038/s41467-024-51860-2.
Wennan Zhao  1 ,  Xue Wang  2  3 ,  Lifeng Han  4 ,  Chunze Zhang  5 ,  Chenxi Wang  4 ,  Dexin Kong  6 ,  Mingzhe Zhang  1 ,  Tong Xu  1 ,  Gen Li  1 ,  Ge Hu  1 ,  Jiahua Luo  1 ,  Sook Wah Yee  7 ,  Jia Yang  7 ,  Andreas Stahl  2 ,  Xin Chen  8  9 ,  Youcai Zhang  10
Affiliations
  • 1. School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China.
  • 2. Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, CA, USA.
  • 3. Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
  • 4. Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
  • 5. Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China.
  • 6. Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China.
  • 7. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.
  • 8. Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI, USA. [email protected].
  • 9. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA. [email protected].
  • 10. School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China. [email protected].
PMID: 39215042 DOI: 10.1038/s41467-024-51860-2
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.

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