氯喹抑制铁蛋白自噬并增强肺癌细胞对化疗药物敏感性的研究  

Chloroquine Inhibits Deferoxamine-induced Ferritinophagy and Potentiates The Cytotoxicity of Chemotherapy Drugs in Lung Cancer Cells

作　　者：王永伟 肖敏 张瑀 霍艳武 卫涛涛[1,2] WANG Yong-Wei;XIAO Min;ZHANG Yu;HUO Yan-Wu;WEI Tao-Tao(National Laboratory of Biomacromolecules,Institute of Biophysics,Chinese Academy of Sciences,Beijing 100101,China;University of Chinese Academy of Sciences,Beijing 100049,China)

机构地区：[1]中国科学院生物物理研究所,生物大分子国家重点实验室,北京100101 [2]中国科学院大学,北京100049

出　　处：《生物化学与生物物理进展》2022年第2期370-380,共11页Progress In Biochemistry and Biophysics

基　　金：国家重点研发计划(2019YFA0508602);国家自然科学基金(92054108,22027810);生物大分子国家重点实验室基金资助项目。

摘　　要：目的肺癌的发病率和致死率高居世界恶性肿瘤首位。尽管肺癌的诊断与治疗治疗已取得进展,但其发病率和致死率仍呈逐年上升的趋势,因此急需寻找有效的干预靶标和治疗手段。方法本文验证了通过自噬抑制剂干预铁蛋白自噬、增加肺癌细胞对化疗药物敏感性的多药联用策略。通过免疫印迹分析及免疫荧光测定了细胞中铁蛋白的自噬性降解(铁蛋白自噬),通过分析细胞数量及细胞周期测定了细胞增殖,通过分析细胞耗氧速率评估了细胞线粒体氧化磷酸化水平。结果铁螯合剂去铁胺可诱导肿瘤细胞发生铁蛋白自噬;氯喹等自噬抑制剂可有效抑制去铁胺诱导的铁蛋白降解,显著抑制肿瘤细胞线粒体氧化磷酸化,并引发细胞周期阻滞、抑制细胞增殖;去铁胺、氯喹与一线化疗药物顺铂或依托泊苷的联合给药可显著增强化疗药物对肺癌细胞的毒性。结论通过自噬抑制剂和铁螯合剂干预细胞铁代谢有望成为提升肺癌化疗治疗效果的潜在新策略。Objective Lung cancer is one of the most commonly diagnosed cancers and the leading cause of cancer deaths worldwide. Despite significant advancements in combined therapy, the numbers of lung cancer cases and deaths continue to rise.Thus, novel therapeutic strategies are necessary to improve cure rates. Methods The effect of concomitant use of deferoxamine and chloroquine with frontline chemotherapy drugs was evaluated in lung cancer cells. The autophagy-dependent degradation of ferritin(i.e. ferritinophagy) was determined by western blot and immunofluorescence. The cell proliferation was quantified by cell member and cell cycle. The mitochondrial oxidative phosphorylation was determined by measuring the cellular oxygen consumption.Results The iron chelator deferoxamine induced ferritinophagy in cancer cells, and this process was blocked by chloroquine, an anti-malaria drug. Exposure of lung cancer cells to deferoxamine and chloroquine together inhibited mitochondrial oxidative phosphorylation, caused the accumulation of G1 phase cells and blocked cell proliferation. More importantly, the use of deferoxamine and chloroquine concomitantly with cisplatin or etoposide resulted in a significant increase in cytotoxicity in lung cancer cells when compared with the same concentration of cisplatin or etoposide alone. Conclusion These data indicate the efficacy of targeting ferritinophagy for the sensitization of iron-addicted cancer cells to chemotherapy, and introduce a potential targeted therapeutic approach for the treatment of cancer.

关 键 词：肺癌 铁蛋白自噬 去铁胺 氯喹 化疗 

分 类 号：R734.2[医药卫生—肿瘤] Q28[医药卫生—临床医学]