SLC13A3 is a major effector downstream of activated β-catenin in liver cancer pathogenesis
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.
Authors
- Chunze Zhang (ORCID: https://orcid.org/0000-0002-2063-5631)
- Sook Wah Yee (ORCID: https://orcid.org/0000-0001-8121-8746)
- Jiahua Luo (ORCID: https://orcid.org/0000-0002-7911-5841)
- Hu Ge (ORCID: https://orcid.org/0000-0002-5424-5172)
- Lifeng Han (ORCID: https://orcid.org/0000-0002-9464-2850)
- Tong Xu (ORCID: https://orcid.org/0000-0002-8055-1448)
- Gen Li (ORCID: https://orcid.org/0000-0003-3625-2210)
- Kong De (ORCID: https://orcid.org/0000-0003-0744-116X)
- Mingzhe Zhang (ORCID: https://orcid.org/0000-0002-6987-5572)
- Chenxi Wang (ORCID: https://orcid.org/0000-0002-1451-3101)
- Xin Chen (ORCID: https://orcid.org/0000-0002-9588-0164)
- Wennan Zhao
- Jia Yang (ORCID: https://orcid.org/0000-0002-3992-4070)
- Andreas Stahl (ORCID: https://orcid.org/0000-0002-9096-3024)
- Youcai Zhang (ORCID: https://orcid.org/0000-0001-9919-6442)
- Xue Wang (ORCID: https://orcid.org/0000-0003-3145-9925)
Institutions
- University of Hawaiʻi at Mānoa (US)
- Tianjin University of Traditional Chinese Medicine (CN)
- Tianjin University of Science and Technology (CN)
- University of Hawaii System (US)
- University of California, San Francisco (US)
- Cancer Center of Hawaii (US)
- Tianjin People's Hospital (CN)
- University of Hawaii Cancer Center
- Tianjin Medical University (CN)
- University of California, Berkeley (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-30
- DOI
- https://doi.org/10.1038/s41467-024-51860-2
- Citations
- 17
- Primary Topic
- Amino Acid Enzymes and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 5.01
Funders
- Foundation for the National Institutes of Health
- National Natural Science Foundation of China
- National Institutes of Health