Oncogenic β-catenin-driven liver cancer is susceptible to methotrexate-mediated disruption of nucleotide synthesis  

作　　者：Fangming Liu Yuting Wu Baohui Zhang Shuhui Yang Kezhuo Shang Jie Li Pengju Zhang Weiwei Deng Linlin Chen Liang Zheng Xiaochen Gai Hongbing Zhang 

机构地区：[1]Department of Physiology,State Key Laboratory of Common Mechanism Research for Major Diseases,Haihe Laboratory of Cell Ecosystem,Institute of Basic Medical Sciences and School of Basic Medicine,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100005,China [2]Department of Physiology,Institute of Basic Medical Sciences and School of Basic Medicine,Graduate School of Peking Union Medical College,Chinese Academy of Medical Sciences,Beijing,100005,China [3]Department of Physiology,School of Life Science,China Medical University,Shenyang,Liaoning 110122,China [4]School of Life Sciences,Westlake University,Hangzhou,Zhejiang 310024,China [5]Key Laboratory of Pediatric Hematology and Oncology,Ministry of Health,Institute of Pediatric Translational Medicine,Shanghai Children’s Medical Center,Shanghai Jiao Tong School of Medicine,Shanghai 200127,China

出　　处：《Chinese Medical Journal》2024年第2期181-189,共9页中华医学杂志（英文版）

基　　金：supported by grants from the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(No.2021-1-I2M-018);the Haihe Laboratory of Cell Ecosystem Innovation Fund(No.22HHXBSS00012);the National Natural Science Foundation of China(Nos.81730078 and 81872287)

摘　　要：Background:Liver cancer is largely resistant to chemotherapy.This study aimed to identify the effective chemotherapeutics forβ-catenin-activated liver cancer which is caused by gain-of-function mutation of catenin beta 1(CTNNB1),the most frequently altered proto-oncogene in hepatic neoplasms.Methods:Constitutiveβ-catenin-activated mouse embryonic fibroblasts(MEFs)were established by deleting exon 3(β-catenin^(Δ(ex3)/+)),the most common mutation site in CTNNB1 gene.A screening of 12 widely used chemotherapy drugs was conducted for the ones that selectively inhibitedβ-catenin^(Δ(ex3)/+)but not for wild-type MEFs.Untargeted metabolomics was carried out to examine the alterations of metabolites in nucleotide synthesis.The efficacy and selectivity of methotrexate(MTX)onβ-catenin-activated human liver cancer cells were determined in vitro.Immuno-deficient nude mice subcutaneously inoculated withβ-catenin wild-type or mutant liver cancer cells and hepatitis B virus(HBV);β-catenin^(lox(ex3)/+)mice were used,respectively,to evaluate the efficacy of MTX in the treatment ofβ-catenin mutant liver cancer.Results:MTX was identified and validated as a preferential agent against the proliferation and tumor formation ofβ-catenin-activated cells.Boosted nucleotide synthesis was the major metabolic aberration inβ-catenin-active cells,and this alteration was also the target of MTX.Moreover,MTX abrogated hepatocarcinogenesis of HBV;β-catenin^(lox(ex3)/+)mice,which stimulated concurrent Ctnnb1-activated mutation and HBV infection in liver cancer.Conclusion:MTX is a promising chemotherapeutic agent forβ-catenin hyperactive liver cancer.Since repurposing MTX has the advantages of lower risk,shorter timelines,and less investment in drug discovery and development,a clinical trial is warranted to test its efficacy in the treatment ofβ-catenin mutant liver cancer.

关 键 词：Liver cancer β-catenin METHOTREXATE Nucleotide synthesis Chemotherapy 

分 类 号：R735.7[医药卫生—肿瘤]