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SLC13A3 is a major effector downstream of activated β-catenin in liver cancer pathogenesis.
- Source :
- Nature Communications; 8/30/2024, Vol. 15 Issue 1, p1-21, 21p
- Publication Year :
- 2024
-
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. The therapeutic approaches directly targeting activated β-catenin in liver cancers are restricted by toxicities. Here the authors identify that the solute carrier transporter SLC13A3 is upregulated by activation of β-catenin and silencing of SLC13A3 induces ferroptosis, which could be exploited as a therapeutic opportunity in β-catenin-driven liver cancers. [ABSTRACT FROM AUTHOR]
- Subjects :
- LIVER cancer
LIVER cells
CARCINOGENESIS
GENE expression
SMALL molecules
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 15
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Nature Communications
- Publication Type :
- Academic Journal
- Accession number :
- 179359534
- Full Text :
- https://doi.org/10.1038/s41467-024-51860-2