2. Academic Validation
  3. SLC13A3 is a major effector downstream of activated β-catenin in liver cancer pathogenesis

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

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. xinchen3@hawaii.edu.
  • 9 Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA. xinchen3@hawaii.edu.
  • 10 School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China. youcai.zhang@tju.edu.cn.
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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