Department of Surgery, School of Medicine, University of Pittsburgh, 5117 Centre Ave, Pittsburgh, PA, 15213, USA.
Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
Apoptosis. 2020 Oct;25(9-10):625-631. doi: 10.1007/s10495-020-01627-z.
Ferroptosis is considered a distinctive form of cell death compared to other types of death such as apoptosis. It is known to result from iron-dependent accumulation of lipid peroxides rather than caspase activation. However, we reported recently that ferroptosis interplays with apoptosis. In this study, we investigated a possible mechanism of this interplay between ferroptosis and apoptosis. Results from our studies reveal that combined treatment of the ferroptotic agent erastin and the apoptotic agent TRAIL effectively disrupted mitochondrial membrane potential (ΔΨm) and subsequently promoted caspase activation. The alterations of mitochondrial membrane potential are probably due to an increase in oligomerization of BAX and its accumulation at the mitochondria during treatment with erastin and TRAIL. Interestingly, the combined treatment-promoted apoptosis was effectively inhibited in BAX-deficient HCT116 cells, but not BAK-deficient cells. These results indicate that the BAX-associated mitochondria-dependent pathway plays a pivotal role in erastin-enhanced TRAIL-induced apoptosis.
铁死亡被认为是一种独特的细胞死亡形式，与细胞凋亡等其他类型的死亡形式不同。它是已知的由铁依赖性脂质过氧化物积累而不是半胱天冬酶激活引起的。然而，我们最近报道铁死亡与细胞凋亡相互作用。在这项研究中，我们研究了铁死亡和细胞凋亡之间相互作用的可能机制。我们的研究结果表明，铁死亡剂 erastin 和凋亡剂 TRAIL 的联合处理有效地破坏了线粒体膜电位（ΔΨm），并随后促进了半胱天冬酶的激活。线粒体膜电位的改变可能是由于 erastin 和 TRAIL 处理时 BAX 的寡聚化增加及其在线粒体中的积累所致。有趣的是，BAX 缺陷型 HCT116 细胞中的联合处理促进的细胞凋亡被有效抑制，但 BAK 缺陷型细胞则没有。这些结果表明，BAX 相关的线粒体依赖性途径在 erastin 增强 TRAIL 诱导的细胞凋亡中发挥关键作用。
