Ferroptosis inducers enhanced cuproptosis induced by copper ionophores in primary liver cancer

Journal of Experimental & Clinical Cancer Research

Research

Xian Wang¹  Hongchuan Jin²  Qi Wei²  Liyuan Zhu²  Weikai Wang²  Xin Jiang²  Kaizhong Lu²  Lifeng Feng² 

[1] Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China;Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang Province, Sir Run Run Shaw Hospital, School of Medicine, Cancer Center of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang, China;

关键词: Cuproptosis;    Ferroptosis;    Copper ionophores;    Lipoylation;    Ferredoxin 1 (FDX1);   

DOI  :  10.1186/s13046-023-02720-2

 received in 2023-03-11, accepted in 2023-05-24,  发布年份 2023

来源: Springer

【 摘 要 】

IntroductionCuproptosis and ferroptosis are the two newly defined metal-related regulated cell death. However, the crosstalk between cuproptosis and ferroptosis is obscure.Materials and methodsWe analyzed the effect of ferroptosis inducers on copper ionophores-induced cell death through CCK-8 assay. Cuproptosis was studied using immunofluorescence and protein soluble-insoluble fraction isolation. GSH assay, qRT-PCR and western blot were adopted to explore the machinery of ferroptosis inducers enhanced cuproptosis. And mouse xenograft model was built to detect the synergy effect of elesclomol-Cu and sorafenib in vivo.ResultsHerein we found that ferroptosis inducers sorafenib and erastin could enhance cuproptosis in primary liver cancer cells by increasing copper dependent lipoylated protein aggregation. Mechanically, sorafenib and erastin upregulated protein lipoylation via suppressing mitochondrial matrix-related proteases mediated ferredoxin 1 (FDX1) protein degradation, and reduced intracellular copper chelator glutathione (GSH) synthesis through inhibiting cystine importing.Discussion/ConclusionOur findings proposed that combination of ferroptosis inducers and copper ionophores to co-targeting ferroptosis and cuproptosis could be a novel therapeutic strategy for primary liver cancer.

【 授权许可】

CC BY   
© The Author(s) 2023

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