Ferroptosis is a novel form of cell death, which is distinguished from apoptosis and necrosis, and characterized by accumulation of lipid-based reactive oxygen species (ROS) in an iron-dependent manner. Erastin, a small molecule, was widely reported to trigger ferroptosis in various kinds of cancer cells, including pancreatic cancer cells by inducing ROS accumulation. However, how erastin treatment exerts cytotoxicity is not still fully understood. In this study, the effects of erastin in causing pancreatic cancer cell death via inducing ferroptosis and apoptosis are investigated. As expected, erastin treatment caused ROS accumulation, increase in iron concentration and non-apoptotic cell death, which is different from that of induced by apoptosis inducer, staurosporine. Interestingly, erastin treatment caused the upregulation of clusterin, which contributes to the regulation of malignant behaviors of pancreatic cancer, including preventing apoptosis and inducing chemoresistance. Without erastin treatment, overexpressed clusterin significantly promoted cell proliferation, which is consistent with its cytoprotective roles. After erastin treatment, overexpressed clusterin decreased erastin-induced ROS accumulation and cell death. By measuring iron concentration, reduced glutathione (GSH) and glutathione peroxidase 4 (GPX4), it is revealed that clusterin caused resistance to erastin-induced ferroptosis potentially via maintaining the enzymatic activity of GPX4, without disturbing GSH amount. Thus, ferroptosis inducer, erastin, may crosstalk with apoptotic cell death via regulating clusterin, indicating a more complex regulatory network between ferroptosis and apoptosis.

中文翻译：

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Clusterin 被erastin（一种铁死亡诱导剂）上调，并在胰腺癌细胞中发挥细胞保护作用。


铁死亡是一种新型的细胞死亡形式，与细胞凋亡和坏死不同，其特征是以铁依赖性方式积累脂质活性氧（ROS）。据广泛报道，Erastin 是一种小分子，可通过诱导 ROS 积累来引发各种癌细胞（包括胰腺癌细胞）的铁死亡。然而，erastin治疗如何发挥细胞毒性尚不完全清楚。在这项研究中，研究了erastin通过诱导铁死亡和细胞凋亡导致胰腺癌细胞死亡的作用。正如预期的那样，erastin处理引起ROS积累、铁浓度增加和非凋亡细胞死亡，这与细胞凋亡诱导剂星形孢菌素诱导的细胞死亡不同。有趣的是，erastin治疗引起簇蛋白上调，这有助于调节胰腺癌的恶性行为，包括防止细胞凋亡和诱导化疗耐药。在没有erastin处理的情况下，过度表达的凝聚素显着促进细胞增殖，这与其细胞保护作用一致。经erastin处理后，过度表达的clusterin减少了erastin诱导的ROS积累和细胞死亡。通过测量铁浓度、还原型谷胱甘肽 (GSH) 和谷胱甘肽过氧化物酶 4 (GPX4)，结果表明，簇蛋白可能通过维持 GPX4 的酶活性，在不干扰 GSH 含量的情况下，对erastin诱导的铁死亡产生抵抗力。因此，铁死亡诱导剂erastin可能通过调节簇蛋白与凋亡细胞死亡相互影响，表明铁死亡和细胞凋亡之间存在更复杂的调节网络。