{"title":"SLC13A3 是肝癌发病机制中活化的 β-catenin 下游的主要效应因子","authors":"Wennan Zhao, Xue Wang, Lifeng Han, Chunze Zhang, Chenxi Wang, Dexin Kong, Mingzhe Zhang, Tong Xu, Gen Li, Ge Hu, Jiahua Luo, Sook Wah Yee, Jia Yang, Andreas Stahl, Xin Chen, Youcai Zhang","doi":"10.1038/s41467-024-51860-2","DOIUrl":null,"url":null,"abstract":"<p>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. <i>SLC13A3</i> expression is elevated in human liver cancer samples with gain of function (GOF) mutant <i>CTNNB1</i>, the gene encoding β-catenin. Activation of β-catenin up-regulates <i>SLC13A3</i>, leading to intracellular accumulation of endogenous SLC13A3 substrates. SLC13A3 is identified as a low-affinity transporter for glutathione (GSH). Silencing of <i>SLC13A3</i> downregulates the leucine transporter <i>SLC7A5</i> via c-MYC signaling, leading to leucine depletion and mTOR inactivation. Furthermore, silencing of <i>SLC13A3</i> depletes GSH and induces autophagic ferroptosis in β-catenin-activated liver cancer cells. Importantly, both genetic inhibition of <i>SLC13A3</i> 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 <i>CTNNB1</i> mutations.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":null,"pages":null},"PeriodicalIF":14.7000,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"SLC13A3 is a major effector downstream of activated β-catenin in liver cancer pathogenesis\",\"authors\":\"Wennan Zhao, Xue Wang, Lifeng Han, Chunze Zhang, Chenxi Wang, Dexin Kong, Mingzhe Zhang, Tong Xu, Gen Li, Ge Hu, Jiahua Luo, Sook Wah Yee, Jia Yang, Andreas Stahl, Xin Chen, Youcai Zhang\",\"doi\":\"10.1038/s41467-024-51860-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>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. <i>SLC13A3</i> expression is elevated in human liver cancer samples with gain of function (GOF) mutant <i>CTNNB1</i>, the gene encoding β-catenin. Activation of β-catenin up-regulates <i>SLC13A3</i>, leading to intracellular accumulation of endogenous SLC13A3 substrates. SLC13A3 is identified as a low-affinity transporter for glutathione (GSH). Silencing of <i>SLC13A3</i> downregulates the leucine transporter <i>SLC7A5</i> via c-MYC signaling, leading to leucine depletion and mTOR inactivation. Furthermore, silencing of <i>SLC13A3</i> depletes GSH and induces autophagic ferroptosis in β-catenin-activated liver cancer cells. Importantly, both genetic inhibition of <i>SLC13A3</i> 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 <i>CTNNB1</i> mutations.</p>\",\"PeriodicalId\":19066,\"journal\":{\"name\":\"Nature Communications\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":14.7000,\"publicationDate\":\"2024-08-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature Communications\",\"FirstCategoryId\":\"103\",\"ListUrlMain\":\"https://doi.org/10.1038/s41467-024-51860-2\",\"RegionNum\":1,\"RegionCategory\":\"综合性期刊\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MULTIDISCIPLINARY SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Communications","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1038/s41467-024-51860-2","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
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.
期刊介绍:
Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.