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Overcoming the compensatory elevation of NRF2 renders hepatocellular carcinoma cells more vulnerable to disulfiram/copper-induced ferroptosis.

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收录情况： ◇ SCIE

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机构： [1]Laboratory Medicine Center, Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China [2]Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310005, China [3]Department of Central Laboratory, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China [4]Laboratory Medicine Center, Clinical Research Institute, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China [5]The Key Laboratory for Human Disease Gene Study of Sichuan Province, Prenatal Diagnosis Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China [6]Phase I Clinical Research Center, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China

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关键词： Ferroptosis Disulfiram Hepatocellular carcinoma Oxidative stress Sorafenib

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Hepatocellular carcinoma (HCC) is one of the paramount causes of cancer-related death worldwide. Despite recent advances have been made in clinical treatments of HCC, the general prognosis of patients remains poor. Therefore, it is imperative to develop a less toxic and more effective therapeutic strategy. Currently, series of cellular, molecular, and pharmacological experimental approaches were utilized to address the unrecognized characteristics of disulfiram (DSF), pursuing the goal of repurposing DSF for cancer therapy. We found that DSF/Cu selectively exerted an efficient cytotoxic effect on HCC cell lines, and potently inhibited migration, invasion, and angiogenesis of HCC cells. Importantly, we confirmed that DSF/Cu could intensively impair mitochondrial homeostasis, increase free iron pool, enhance lipid peroxidation, and eventually result in ferroptotic cell death. Of note, a compensatory elevation of NRF2 accompanies the process of ferroptosis, and contributes to the resistance to DSF/Cu. Mechanically, we found that DSF/Cu dramatically activated the phosphorylation of p62, which facilitates competitive binding of Keap1, thus prolonging the half-life of NRF2. Notably, inhibition of NRF2 expression via RNA interference or pharmacological inhibitors significantly facilitated the accumulation of lipid peroxidation, and rendered HCC cells more sensitive to DSF/Cu induced ferroptosis. Conversely, fostering NRF2 expression was capable of ameliorating the cell death activated by DSF/Cu. Additionally, DSF/Cu could strengthen the cytotoxicity of sorafenib, and arrest tumor growth both in vitro and in vivo, by simultaneously inhibiting the signal pathway of NRF2 and MAPK kinase. In summary, these results provide experimental evidence that inhibition of the compensatory NRF2 elevation strengthens HCC cells more vulnerable to DSF/Cu induced ferroptosis, which facilitates the synergistic cytotoxicity of DSF/Cu and sorafenib.Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.

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出版当年[2021]版：

大类 | 1 区

生物学

小类 | 1 区生化与分子生物学

最新[2023]版：

大类 | 1 区

生物学

小类 | 1 区生化与分子生物学

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出版当年[2021]版：

Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

最新[2023]版：

Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

影响因子： 10.7 最新[2023版] 11.7 最新五年平均 10.787 出版当年[2021版] 11.271 出版当年五年平均 11.799 出版前一年[2020版] 11.4 出版后一年[2022版]

第一作者：

第一作者机构： [1]Laboratory Medicine Center, Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China [2]Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310005, China

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通讯作者：

通讯机构： [1]Laboratory Medicine Center, Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China [3]Department of Central Laboratory, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China [4]Laboratory Medicine Center, Clinical Research Institute, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China [6]Phase I Clinical Research Center, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China [*1]Laboratory Medicine Center, Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, 310014, China [*2]Phase I Clinical Research Center, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China

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Overcoming the compensatory elevation of NRF2 renders hepatocellular carcinoma cells more vulnerable to disulfiram/copper-induced ferroptosis. $(function () { $("[data-toggle='tooltip']").tooltip(); });

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Overcoming the compensatory elevation of NRF2 renders hepatocellular carcinoma cells more vulnerable to disulfiram/copper-induced ferroptosis.