Chen Yingying, Wang Fujue, Wu Pengqiang, Gong Shuaige, Gao Jie, Tao Huan, Shen Qianqing, Wang Shuoting, Zhou Zhencang, Jia Yongqian
Department of Hematology and Research Laboratory of Hematology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China.
Department of Hematology, The First Affiliated Hospital of University of South China, Hengyang 421001, Hunan, China.
Cell Signal. 2021 Dec;88:110167. doi: 10.1016/j.cellsig.2021.110167. Epub 2021 Oct 7.
Artesunate (ART), a water-soluble derivative of artemisinin, has been reported to exert antineoplastic effects via diverse mechanisms in various types of cancer. Therefore, understanding the underlying mechanism of action of ART in distinct cancer types is indispensable to optimizing the therapeutic application of ART for different types of cancer. The present study aimed to investigate the cellular and molecular mechanisms responsible for the antineoplastic effects of ART in diffuse large B cell lymphoma (DLBCL) cells. Cell proliferation was measured using Cell Counting Kit-8 and colony formation assays. The levels of apoptosis and cell cycle distribution were investigated using flow cytometry. In addition, western blotting was used to analyze the expression levels of ART-induced apoptosis-, autophagy- and ferroptosis-related proteins. Monodansylcadaverine staining was performed to determine the levels of autophagy. Moreover, malondialdehyde and reactive oxygen species assays were used to determine the levels of ferroptosis. The results of the present study revealed that ART inhibited proliferation, and induced apoptosis, cell cycle arrest, autophagy and ferroptosis in DLBCL cells. Pharmacological inhibition of autophagy and ferroptosis alleviated the increased levels of apoptosis induced by ART. Notably, ART was found to exert its effects via inhibition of STAT3 activation. The genetic knockdown of STAT3 enhanced ART-induced autophagy and ferroptosis, and concomitantly upregulated the expression levels of apoptosis- and cell cycle-related proteins. In conclusion, the findings of the current study suggested that ART may induce apoptosis and cell cycle arrest to inhibit cell proliferation, and regulate autophagy and ferroptosis via impairing the STAT3 signaling pathway in DLBCL cells.
青蒿琥酯（ART）是青蒿素的水溶性衍生物，据报道其可通过多种机制在各类癌症中发挥抗肿瘤作用。因此，了解ART在不同癌症类型中的潜在作用机制对于优化其在不同类型癌症中的治疗应用至关重要。本研究旨在探讨ART在弥漫性大B细胞淋巴瘤（DLBCL）细胞中发挥抗肿瘤作用的细胞和分子机制。使用细胞计数试剂盒-8和集落形成试验检测细胞增殖。采用流式细胞术研究细胞凋亡水平和细胞周期分布。此外，使用蛋白质免疫印迹法分析ART诱导的凋亡、自噬和铁死亡相关蛋白的表达水平。进行单丹磺酰尸胺染色以确定自噬水平。此外，使用丙二醛和活性氧检测来确定铁死亡水平。本研究结果表明，ART抑制DLBCL细胞的增殖，并诱导其凋亡、细胞周期阻滞、自噬和铁死亡。自噬和铁死亡的药理学抑制减轻了ART诱导的凋亡水平升高。值得注意的是，发现ART通过抑制STAT3激活发挥其作用。STAT3的基因敲低增强了ART诱导的自噬和铁死亡，并同时上调了凋亡和细胞周期相关蛋白的表达水平。总之，本研究结果表明，ART可能通过诱导凋亡和细胞周期阻滞来抑制细胞增殖，并通过损害DLBCL细胞中的STAT3信号通路来调节自噬和铁死亡。
