Zhou Yulu, Yang Jingjing, Chen Cong, Li Zhaoqing, Chen Yongxia, Zhang Xun, Wang Linbo, Zhou Jichun
Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China.
Front Pharmacol. 2021 May 10;12:670224. doi: 10.3389/fphar.2021.670224. eCollection 2021.
Ferroptosis, which is characterized by the accumulation of intracellular iron and subsequent lipid peroxidation, is a newly discovered form of regulated cell death and plays an important role in tumor suppression. Herein, we showed that Polyphyllin III, which is a major saponin extracted from rhizomes, exerted its proliferation-inhibitory effect on MDA-MB-231 triple-negative breast cancer cells mainly through ACSL4-mediated lipid peroxidation elevation and ferroptosis induction. ACSL4 deletion partly attenuated Polyphyllin III-induced ferroptosis. Polyphyllin III treatment also induced KLF4-mediated protective upregulation of xCT, which is the negative regulator of ferroptosis. Interestingly, combination with the xCT inhibitor sulfasalazine (SAS) or downregulation of KLF4 sensitized MDA-MB-231 cells to Polyphyllin III. Furthermore, xenograft models, SAS significantly sensitized MDA-MB-231 breast cancer cells to Polyphyllin III, likely by enhancing intracellular lipid peroxidation and ferroptosis. The results of this study collectively demonstrated that Polyphyllin III exerts its anticancer effect by inducing ferroptosis via ACSL4 in MDA-MB-231 breast cancer cells. More importantly, we observed for the first time that KLF4-mediated xCT upregulation serves as negative feedback during ferroptosis progression, which might contribute to drug resistance in cancer treatment.
铁死亡是一种新发现的程序性细胞死亡形式，其特征是细胞内铁的积累及随后的脂质过氧化，在肿瘤抑制中发挥重要作用。在此，我们发现从根茎中提取的主要皂苷重楼皂苷III对MDA-MB-231三阴性乳腺癌细胞发挥增殖抑制作用，主要是通过ACSL4介导的脂质过氧化升高和铁死亡诱导。ACSL4缺失部分减弱了重楼皂苷III诱导的铁死亡。重楼皂苷III处理还诱导了KLF4介导的铁死亡负调节因子xCT的保护性上调。有趣的是，与xCT抑制剂柳氮磺胺吡啶（SAS）联合使用或KLF4下调使MDA-MB-231细胞对重楼皂苷III敏感。此外，在异种移植模型中，SAS可能通过增强细胞内脂质过氧化和铁死亡，使MDA-MB-231乳腺癌细胞对重楼皂苷III显著敏感。本研究结果共同表明，重楼皂苷III通过在MDA-MB-231乳腺癌细胞中经由ACSL4诱导铁死亡发挥抗癌作用。更重要的是，我们首次观察到KLF4介导的xCT上调在铁死亡进程中作为负反馈，这可能导致癌症治疗中的耐药性。
