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作 者:Yi Yu Yuanyuan Ren Caihua Wang Zhuozhuo Li Fanglin Niu Zi Li Qiang Ye Jiangxia Wang Yuan Yan Ping Liu Lu Qian Yuyan Xiong
机构地区:[1]Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases,Xi’an No.3 Hospital,Faculty of Life Sciences and Medicine,Northwest University,Xi’an 710018,China [2]Key Laboratory of Resource Biology and Biotechnology in Western China,Ministry of Education,School of Medicine,Northwest University,Xi’an 710069,China [3]Department of Endocrinology,Xi’an No.3 Hospital,the Affiliated Hospital of Northwest University,Northwest University,Xi’an 710069,China
出 处:《Acta Biochimica et Biophysica Sinica》2022年第11期1658-1670,共13页生物化学与生物物理学报(英文版)
基 金:This work was supported by grants from the National Natural Science Foundation of China(No.82103589);the Natural Science Foundation of Shaanxi Province(Nos.2020JQ-611 and 2021JQ-458);the Special Scientific Research Plan for Emergency Public Health Safety 2020 of Shaanxi Provincial Department of Education(No.20JG034);Scientific Research Foundation 2019 for the Returned Overseas Scholars of Shaanxi Province and High-level Talent Programs of Shaanxi Province。
摘 要:Ferroptosis,a newly defined and iron-dependent cell death,morphologically and biochemically differs from other cell deaths.Melanoma is a serious type of skin cancer,and the poor efficacy of current therapies causes a major increase in mortality.Sorafenib,a multiple kinase inhibitor,has been evaluated in clinical phase trials of melanoma patients,which shows modest efficacy.Emerging evidence has demonstrated that arginase 2(Arg2),type 2 of arginase,is elevated in various types of cancers including melanoma.To investigate the role and underlying mechanism of Arg2 in sorafenib-induced ferroptosis in melanoma,reverse transcriptase-quantitative polymerase chain reaction,western blot analysis,adenovirus and lentivirus transduction,and in vivo tumor homograft model experiments were conducted.In this study,we show that sorafenib treatment leads to melanoma cell death and a decrease in Arg2 at both the mRNA and protein levels.Knockdown of Arg2 increases lipid peroxidation,which contributes to ferroptosis,and decreases the phosphorylation of Akt.In contrast,overexpression of Arg2 rescues sorafenib-induced ferroptosis,which is prevented by an Akt inhibitor.In addition,genetic and pharmacological suppression of Arg2 is able to ameliorate the anticancer activity of sorafenib in melanoma cells in vitro and in tumor homograft models.We also show that Arg2 suppresses ferroptosis by activating the Akt/GPX4 signaling pathway,negatively regulating sorafenib-induced cell death in melanoma cells.Our study not only uncovers a novel mechanism of ferroptosis in melanoma but also provides a new strategy for the clinical applications of sorafenib in melanoma treatment.
关 键 词:Arginase 2 SORAFENIB ferroptosis lipid peroxidation MELANOMA
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