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

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

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Background:Liver cancer is largely resistant to chemotherapy.This study aimed to identify the effective chemotherapeutics for p-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:Constitutive p-catenin-activated mouse embryonic fibroblasts(MEFs)were established by deleting exon 3(β-catenin△(ex3)/+),the most common mutation site in CTNNB1 gene.A screening of 12 widely used chemotherapy drugs was conducted for the ones that selectively inhibited β-catenin△(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)on p-catenin-activated human liver cancer cells were determined in vitro.Immuno-deficient nude mice subcutaneously inoculated with p-catenin wild-type or mutant liver cancer cells and hepatitis B virus(HBV);β-cateninlox(ex3)/+mice were used,respectively,to evaluate the efficacy of MTX in the treatment of p-catenin mutant liver cancer.Results:MTX was identified and validated as a preferential agent against the proliferation and tumor formation of p-catenin-activated cells.Boosted nucleotide synthesis was the major metabolic aberration in β-catenin-active cells,and this alteration was also the target of MTX.Moreover,MTX abrogated hepatocarcinogenesis of HBV;β-cateninlox(ex3)+mice,which stimulated concurrent Ctnnb1-activated mutation and HBV infection in liver cancer.Conclusion:MTX is a promising chemotherapeutic agent for p-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 of p-catenin mutant liver cancer.

Liver cancerp-cateninMethotrexateNucleotide synthesisChemotherapy

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

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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

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

Department of Physiology,School of Life Science,China Medical University,Shenyang,Liaoning 110122,China

School of Life Sciences,Westlake University,Hangzhou,Zhejiang 310024,China

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

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Chinese Academy of Medical Sciences Innovation Fund for Medical SciencesHaihe Laboratory of Cell Ecosystem Innovation FundNational Natural Science Foundation of ChinaNational Natural Science Foundation of China

2021-1-I2M-01822HHXBSS000128173007881872287

2024

10.1097/CM9.0000000000002816

中华医学杂志(英文版)
中华医学会

中华医学杂志(英文版)

CSTPCD
影响因子：0.838
ISSN：0366-6999
年,卷(期)：2024.137(2)
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