Department of Gastroenterology, Shanghai Tenth People's Hospital Affiliated to Tongji University, Tongji University, School of Medicine, Shanghai, China.
J Leukoc Biol. 2021 Aug;110(2):301-314. doi: 10.1002/JLB.3MA1220-815RRR.
IFNγ released from CD8 T cells or natural killer cells plays a crucial role in antitumor host immunity. Several studies have found that IFNγ is involved in regulating tumor cell proliferation and apoptosis. However, few studies have examined its role in cell ferroptosis. Here, we found that IFNγ treatment enhanced glutathione depletion, promoted cell cycle arrested in G0/G1 phase, increased lipid peroxidation, and sensitized cells to ferroptosis activators. Additionally, IFNγ down-regulated the mRNA and protein levels of SLC3A2 and SLC7A11, two subunits of the glutamate-cystine antiporter system xc via activating the JAK/STAT pathway in hepatocellular carcinoma (HCC) cell lines. Furthermore, IFNγ increased reactive oxygen species levels and decreased mitochondiral membrane potential in Bel7402 and HepG2 cells. These changes were accompanied by decreased system xc activity. Cancer cells exposed to TGFβ1 for 48 h showed sensitization to IFNγ + erastin-induced ferroptosis, with decreased system xc expression. In conclusion, IFNγ repressed system xc activation via activating JAK/STAT signaling. Additionally, enhanced lipid peroxidation was associated with altered mitochondrial function in HCC cells. Our findings identified a role for IFNγ in sensitizing HCC cells to ferroptosis, which provided new insights for applying IFNγ as a cancer treatment.
CD8 T 细胞或自然杀伤细胞释放的 IFNγ 在抗肿瘤宿主免疫中发挥着关键作用。有几项研究发现 IFNγ 参与调节肿瘤细胞增殖和凋亡。然而，很少有研究检查其在细胞铁死亡中的作用。在这里，我们发现 IFNγ 处理增强了谷胱甘肽耗竭，促进细胞周期停滞在 G0/G1 期，增加了脂质过氧化，并使细胞对铁死亡激活剂敏感。此外，IFNγ 通过激活 JAK/STAT 通路下调了肝癌 (HCC) 细胞系中谷氨酸-胱氨酸反向转运蛋白系统 xc 的两个亚基 SLC3A2 和 SLC7A11 的 mRNA 和蛋白水平。此外，IFNγ 在 Bel7402 和 HepG2 细胞中增加了活性氧水平并降低了线粒体膜电位。这些变化伴随着系统 xc 活性的降低。暴露于 TGFβ1 48 h 的癌细胞对 IFNγ+erastin 诱导的铁死亡表现出敏感性，系统 xc 表达降低。总之，IFNγ 通过激活 JAK/STAT 信号通路抑制系统 xc 的激活。此外，增强的脂质过氧化与 HCC 细胞中线粒体功能的改变有关。我们的研究结果确定了 IFNγ 在使 HCC 细胞对铁死亡敏感中的作用，这为将 IFNγ 应用于癌症治疗提供了新的见解。
