Interferon gamma-induced apoptosis of head and neck squamous cell carcinoma is connected to indoleamine-2,3-dioxygenase via mitochondrial and ER stress-associated pathways.
Interferon gamma-induced apoptosis of head and neck squamous cell carcinoma is connected to indoleamine-2,3-dioxygenase via mitochondrial and ER stress-associated pathways.
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DOI：
10.1186/s13008-016-0023-4
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发表时间：
2016
期刊：
影响因子：
2.3
通讯作者：
Hassan M
中科院分区：
文献类型：
--
作者：
El Jamal SM;Taylor EB;Abd Elmageed ZY;Alamodi AA;Selimovic D;Alkhateeb A;Hannig M;Hassan SY;Santourlidis S;Friedlander PL;Haikel Y;Vijaykumar S;Kandil E;Hassan M
肿瘤对免疫治疗的反应是细胞因子和效应细胞之间协同作用的结果。干扰素γ（IFNγ）是协调肿瘤免疫反应和相关生物学后果的常见细胞因子之一。尽管 IFNγ 在调节肿瘤免疫中的作用已被广泛记录，但在免疫治疗过程中调节 IFNγ 诱导的细胞死亡的机制尚未详细描述。 IFNγ引发CLS-354和RPMI 2650细胞凋亡，增强吲哚胺2,3-双加氧酶（IDO）的蛋白表达和激活，并抑制血红素加氧酶-1（HO-1）的基础表达。有趣的是，IFNγ诱导线粒体膜电位（Δψm）损失并增加活性氧（ROS）的积累。该细胞因子还诱导 Janus 激酶 (JAK)/信号转导和转录激活剂 (STAT)1、凋亡信号调节激酶 1 (ASK1)、p38、c-jun-N 末端激酶 (JNK) 和 NF-κB 通路以及转录因子 STAT1、干扰素调节因子 1 (IRF1)、AP-1、ATF-2、NF-κB 和 p53 的激活，以及 Noxa 的表达蛋白质。此外，发现 IFNγ 会引发内质网 (ER) 应激，这一点可以通过 caspase-4 的裂解以及蛋白激酶 RNA 样内质网激酶 (PERK) 和肌醇需求 1α (IRE1α) 途径的激活来证明。使用特定的抑制剂，我们确定了 IDO 作为细胞凋亡介质在通过 Noxa 介导的线粒体失调和 ER 应激调节 IFNγ 诱导的头颈鳞状细胞癌 (HNSCC) 细胞凋亡中的潜在作用。除了阐明IDO在细胞凋亡调节中的作用外，我们的研究还为免疫治疗过程中IFNγ诱导HNSCC细胞凋亡的分子机制提供了新的见解。
Tumor response to immunotherapy is the consequence of a concerted crosstalk between cytokines and effector cells. Interferon gamma (IFNγ) is one of the common cytokines coordinating tumor immune response and the associated biological consequences. Although the role of IFNγ in the modulation of tumor immunity has been widely documented, the mechanisms regulating IFNγ-induced cell death, during the course of immune therapy, is not described in detail. IFNγ triggered apoptosis of CLS-354 and RPMI 2650 cells, enhanced the protein expression and activation of indoleamine 2,3-dioxygenase (IDO), and suppressed the basal expression of heme oxygenase-1(HO-1). Interestingly, IFNγ induced the loss of mitochondrial membrane potential (Δψm) and increased accumulation of reactive oxygen species (ROS). The cytokine also induced the activation of Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT)1, apoptosis signal-regulating kinase 1 (ASK1), p38, c-jun-N-terminal kinase (JNK) and NF-κB pathways and the transcription factors STAT1, interferon regulatory factor 1 (IRF1), AP-1, ATF-2, NF-κB and p53, and expression of Noxa protein. Furthermore, IFNγ was found to trigger endoplasmic reticulum (ER) stress as evidenced by the cleavage of caspase-4 and activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol-requiring-1α (IRE1α) pathways. Using specific inhibitors, we identified a potential role for IDO as apoptotic mediator in the regulation of IFNγ-induced apoptosis of head and neck squamous cell carcinoma (HNSCC) cells via Noxa-mediated mitochondrial dysregulation and ER stress. In addition to the elucidation of the role of IDO in the modulation of apoptosis, our study provides new insights into the molecular mechanisms of IFNγ-induced apoptosis of HNSCC cells during the course of immune therapy.