文章：

抑制EIF2α去磷酸化可降低细胞活力并与头颈鳞状细胞癌标准护理化疗药物产生协同作用

Inhibition of EIF2α Dephosphorylation Decreases Cell Viability and Synergizes with Standard-of-Care Chemotherapeutics in Head and Neck Squamous Cell Carcinoma

原文发布日期：9 November 2023

DOI: 10.3390/cancers15225350

类型: Article

开放获取: 是

英文摘要：

Drug resistance is a common cause of therapy failure in head and neck squamous cell carcinoma (HNSCC). One approach to tackling it is by targeting fundamental cellular processes, such as translation. The eukaryotic translation initiation factor 2α (EIF2α) is a key player in canonical translation initiation and integrates diverse stress signals; when phosphorylated, it curbs global protein synthesis. This study evaluates EIF2α expression and phosphorylation in HNSCC. A small-molecule inhibitor of EIF2α dephosphorylation, salubrinal, was tested in vitro, followed by viability assays, flow cytometry, and immunoblot analyses. Patient-derived 3D tumor spheres (PD3DS) were cultured with salubrinal and their viability assessed. Lastly, salubrinal was evaluated with standard-of-care chemotherapeutics. Our analysis of RNA and proteomics data shows elevated EIF2α expression in HNSCC. Immunohistochemical staining reveals increasing EIF2α abundance from premalignant lesions to invasive and metastatic carcinoma. In immunoblots from intraoperative samples, EIF2α expression and steady-state phosphorylation are higher in HNSCC than in neighboring normal tissue. Inhibition of EIF2α dephosphorylation decreases HNSCC cell viability and clonogenic survival and impairs the G1/S transition. Salubrinal also decreases the viability of PD3DS and acts synergistically with cisplatin, 5-fluorouracil, bleomycin, and proteasome inhibitors. Our results indicate that pharmacological inhibition of EIF2α dephosphorylation is a potential therapeutic strategy for HNSCC.

摘要翻译： 

耐药性是头颈部鳞状细胞癌治疗失败的常见原因。针对翻译等基础细胞过程是应对策略之一。真核翻译起始因子2α在经典翻译起始中起关键作用，并能整合多种应激信号；当其磷酸化时可抑制整体蛋白质合成。本研究评估了头颈部鳞状细胞癌中EIF2α的表达与磷酸化状态。通过体外实验测试了EIF2α去磷酸化小分子抑制剂Salubrinal的作用，随后进行细胞活力检测、流式细胞术和免疫印迹分析。将患者来源的3D肿瘤球体与Salubrinal共培养并评估其活力，最后将该抑制剂与标准化疗药物联合评价。RNA和蛋白质组学数据分析显示头颈部鳞状细胞癌中EIF2α表达升高。免疫组化染色表明从癌前病变到浸润性及转移性癌变过程中EIF2α丰度逐渐增加。术中样本免疫印迹显示，头颈部鳞状细胞癌组织的EIF2α表达及稳态磷酸化水平均高于邻近正常组织。抑制EIF2α去磷酸化可降低头颈部鳞状细胞癌细胞活力与克隆形成能力，并阻碍G1/S期转换。Salubrinal还能降低患者来源3D肿瘤球体的活力，且与顺铂、5-氟尿嘧啶、博来霉素及蛋白酶体抑制剂具有协同作用。研究结果表明，药物抑制EIF2α去磷酸化是头颈部鳞状细胞癌的潜在治疗策略。

原文链接：

Inhibition of EIF2α Dephosphorylation Decreases Cell Viability and Synergizes with Standard-of-Care Chemotherapeutics in Head and Neck Squamous Cell Carcinoma