Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Oncoimmunology. 2021 Aug 10;10(1):1962591. doi: 10.1080/2162402X.2021.1962591. eCollection 2021.
Interferon-gamma (IFN-γ) is a major effector molecule of immunity and a common feature of tumors responding to immunotherapy. Active IFN-γ signaling can directly trigger apoptosis and cell cycle arrest in human cancer cells. However, the mechanisms underlying these actions remain unclear. Here, we report that IFN-γ rapidly increases protein synthesis and causes the unfolded protein response (UPR), as evidenced by the increased expression of glucose-regulated protein 78, activating transcription factor-4, and c/EBP homologous protein (CHOP) in cells treated with IFN-γ. The JAK1/2-STAT1 and AKT-mTOR signaling pathways are required for IFN-γ-induced UPR. Endoplasmic reticulum (ER) stress promotes autophagy and restores homeostasis. Surprisingly, in IFN-γ-treated cells, autophagy was impaired at the step of autophagosome-lysosomal fusion and caused by a significant decline in the expression of lysosomal membrane protein-1 and -2 (LAMP-1/LAMP-2). The ER stress inhibitor 4-PBA restored LAMP expression in IFN-γ-treated cells. IFN-γ stimulation activated the protein kinase-like ER kinase (PERK)-eukaryotic initiation factor 2a subunit (eIF2α) axis and caused a reduction in global protein synthesis. The PERK inhibitor, GSK2606414, partially restored global protein synthesis and LAMP expression in cells treated with IFN-γ. We further investigated the functional consequences of IFN-γ-induced ER stress. We show that inhibition of ER stress significantly prevents IFN-γ-triggered apoptosis. CHOP knockdown abrogated IFN-γ-mediated apoptosis. Inhibition of ER stress also restored cyclin D1 expression in IFN-γ-treated cells. Thus, ER stress and the UPR caused by IFN-γ represent novel mechanisms underlying IFN-γ-mediated anticancer effects. This study expands our understanding of IFN-γ-mediated signaling and its cellular actions in tumor cells.
干扰素-γ (IFN-γ) 是免疫的主要效应分子，也是肿瘤对免疫治疗产生反应的共同特征。活性 IFN-γ 信号可直接触发人类癌细胞的凋亡和细胞周期停滞。然而，这些作用的机制尚不清楚。在这里，我们报告 IFN-γ 可快速增加蛋白质合成并引起未折叠蛋白反应 (UPR)，这表现在 IFN-γ 处理的细胞中葡萄糖调节蛋白 78、激活转录因子 4 和 C/EBP 同源蛋白 (CHOP) 的表达增加。JAK1/2-STAT1 和 AKT-mTOR 信号通路是 IFN-γ 诱导 UPR 所必需的。内质网 (ER) 应激促进自噬并恢复平衡。令人惊讶的是，在 IFN-γ 处理的细胞中，自噬在自噬体-溶酶体融合步骤受到损害，这是由于溶酶体膜蛋白 1 和 2 (LAMP-1/LAMP-2) 的表达显著下降所致。ER 应激抑制剂 4-PBA 可恢复 IFN-γ 处理的细胞中的 LAMP 表达。IFN-γ 刺激激活蛋白激酶样内质网激酶 (PERK)-真核起始因子 2a 亚基 (eIF2α) 轴，并导致整体蛋白质合成减少。PERK 抑制剂 GSK2606414 可部分恢复 IFN-γ 处理的细胞中的整体蛋白质合成和 LAMP 表达。我们进一步研究了 IFN-γ 诱导的 ER 应激的功能后果。我们表明，抑制 ER 应激可显著防止 IFN-γ 触发的细胞凋亡。CHOP 敲低可消除 IFN-γ 介导的细胞凋亡。抑制 ER 应激还可恢复 IFN-γ 处理的细胞中环蛋白 D1 的表达。因此，IFN-γ 引起的 ER 应激和 UPR 是 IFN-γ 介导的抗癌作用的新机制。这项研究扩展了我们对 IFN-γ 介导的信号及其在肿瘤细胞中的细胞作用的理解。
