Yuan Bing, Liao Feng, Shi Zhi-Zhou, Ren Yuan, Deng Xiao-Li, Yang Ting-Ting, Li Deng-Yuan, Li Ru-Fang, Pu Dan-Dan, Wang Yu-Jue, Tan Yan, Yang Zhen, Zhang Yun-Hui
Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, People's Republic of China.
Medical School, Kunming University of Science and Technology, Kunming, Yunnan, People's Republic of China.
Onco Targets Ther. 2020 Oct 27;13:10829-10840. doi: 10.2147/OTT.S248492. eCollection 2020.
Lung cancer is the first leading cause of cancer-related deaths both worldwide and in China and threatens human health and quality of life. New drugs and therapeutic methods are urgently needed. Our study evaluated the roles of dihydroartemisinin (DHA) in lung cancer and further explored its underlying mechanisms.
CCK-8, colony formation and trypan blue exclusion assays were used to detect the cell viability, colony formation ability and cell death. qRT-PCR and Western blotting assays were applied to analyze the expressions of key molecules.
DHA inhibited the proliferation and colony formation abilities and enhanced the cell death and induced ferroptosis of lung NCI-H23 and XWLC-05 cancer cells. DHA reduced PRIM2 expression and silencing PRIM2 mimicked the inhibitory roles on proliferation and colony formation and promotive roles on cell death and ferroptosis of DHA in lung NCI-H23 and XWLC-05 cancer cells. We further found that DHA treatment and loss of PRIM2 reduced the GSH level and increased the cellular lipid ROS and mitochondrial MDA levels, and further downregulated the expressions of SLC7A11 and β-catenin in lung cancer cells, respectively. Exogenetic overexpression of PRIM2 recovered the inhibitory effects of DHA on proliferation and colony formation in lung NCI-H23 cancer cells, meanwhile loss of PRIM2 sensitizes NCI-H23 cells to DHA therapy. In vivo experiment further showed that DHA treatment significantly suppressed the tumor growth and downregulated PRIM2 and SLC7A11.
Our study suggested that DHA inhibited the proliferation, colony formation and enhanced cell death and induced ferroptosis of lung cancer cells by inactivating PRIM2/SLC7A11 axis. Loss of PRIM2 induced ferroptosis might developed to be a novel therapeutic method in lung cancer therapy.
肺癌是全球及中国癌症相关死亡的首要原因，威胁着人类健康和生活质量。迫切需要新的药物和治疗方法。我们的研究评估了双氢青蒿素（DHA）在肺癌中的作用，并进一步探讨其潜在机制。
采用CCK-8、集落形成和台盼蓝排斥试验检测细胞活力、集落形成能力和细胞死亡情况。应用qRT-PCR和蛋白质印迹分析关键分子的表达。
DHA抑制肺癌NCI-H23和XWLC-05癌细胞的增殖和集落形成能力，增强细胞死亡并诱导铁死亡。DHA降低PRIM2表达，沉默PRIM2可模拟DHA对肺癌NCI-H23和XWLC-05癌细胞增殖和集落形成的抑制作用以及对细胞死亡和铁死亡的促进作用。我们进一步发现，DHA处理和PRIM2缺失分别降低了肺癌细胞中的谷胱甘肽（GSH）水平，增加了细胞脂质活性氧（ROS）和线粒体丙二醛（MDA）水平，并进一步下调了SLC7A11和β-连环蛋白的表达。外源性过表达PRIM2可恢复DHA对肺癌NCI-H23癌细胞增殖和集落形成的抑制作用，同时PRIM2缺失使NCI-H23细胞对DHA治疗敏感。体内实验进一步表明，DHA处理显著抑制肿瘤生长，并下调PRIM2和SLC7A11表达。
我们的研究表明，DHA通过使PRIM2/SLC7A11轴失活抑制肺癌细胞的增殖、集落形成，增强细胞死亡并诱导铁死亡。PRIM2缺失诱导的铁死亡可能发展成为肺癌治疗的一种新的治疗方法。
