HIV Protease Inhibitors Sensitize Human Head and Neck Squamous Carcinoma Cells to Radiation by Activating Endoplasmic Reticulum Stress.
HIV Protease Inhibitors Sensitize Human Head and Neck Squamous Carcinoma Cells to Radiation by Activating Endoplasmic Reticulum Stress.
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DOI：
10.1371/journal.pone.0125928
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Zhou H
中科院分区：
文献类型：
--
作者：
Liu R;Zhang L;Yang J;Zhang X;Mikkelsen R;Song S;Zhou H
头颈部鳞状细胞癌（HNSCC）是世界上第六大恶性肿瘤。尽管在治疗和外科重建方面取得了重大进展，但在过去几十年中，这种疾病的死亡率没有显著改善。放射治疗是临床综合治疗HNSCC的核心组成部分。然而，肿瘤细胞具有发展辐射抗性的趋势，这是有效治疗的主要障碍。HIV蛋白酶抑制剂（HIV PI）在HNSCC细胞中具有放射增敏活性，但其潜在的细胞/分子机制尚不清楚。我们以前的研究表明，HIV PI通过激活内质网（ER）应激诱导细胞凋亡。本研究的目的是研究ER应激在HIV PI诱导的人HNSCC放射敏感性中的作用。本研究中使用了HNSCC细胞系SQ 20 B和FaDu以及最常用的HIV PI洛匹那韦和利托那韦（L/R）。克隆形成试验测定放射敏感性。使用Cellometer Vision CBA分析细胞活力、凋亡和细胞周期。分别通过真实的RT-PCR和Western印迹分析检测ER应激相关基因（eIF 2 α、CHOP、ATF-4和XBP-1）以及细胞周期相关蛋白cyclin D1的mRNA和蛋白水平。结果表明，L/R剂量依赖性增敏HNSCC细胞的辐射和抑制细胞生长。L/R诱导的ER应激激活与cyclin D1表达下调和细胞周期阻滞于G 0/G1期有关。HIV PI通过激活ER应激和诱导细胞周期停滞使HNSCC细胞对放射治疗敏感。我们的研究结果提供了证据表明，HIV PI可以潜在地与放射联合用于治疗HNSCC。
Human head and neck squamous cell carcinoma (HNSCC) is the sixth most malignant cancer worldwide. Despite significant advances in the delivery of treatment and surgical reconstruction, there is no significant improvement of mortality rates for this disease in the past decades. Radiotherapy is the core component of the clinical combinational therapies for HNSCC. However, the tumor cells have a tendency to develop radiation resistance, which is a major barrier to effective treatment. HIV protease inhibitors (HIV PIs) have been reported with radiosensitizing activities in HNSCC cells, but the underlying cellular/molecular mechanisms remain unclear. Our previous study has shown that HIV PIs induce cell apoptosis via activation of endoplasmic reticulum (ER) stress. The aim of this study was to examine the role of ER stress in HIV PI-induced radiosensitivity in human HNSCC. HNSCC cell lines, SQ20B and FaDu, and the most commonly used HIV PIs, lopinavir and ritonavir (L/R), were used in this study. Clonogenic assay was used to assess the radiosensitivity. Cell viability, apoptosis and cell cycle were analyzed using Cellometer Vision CBA. The mRNA and protein levels of ER stress-related genes (eIF2α, CHOP, ATF-4, and XBP-1), as well as cell cycle related protein, cyclin D1, were detected by real time RT-PCR and Western blot analysis, respectively. The results demonstrated that L/R dose-dependently sensitized HNSCC cells to irradiation and inhibited cell growth. L/R-induced activation of ER stress was correlated to down-regulation of cyclin D1 expression and cell cycle arrest under G0/G1 phase. HIV PIs sensitize HNSCC cells to radiotherapy by activation of ER stress and induction of cell cycle arrest. Our results provided evidence that HIV PIs can be potentially used in combination with radiation in the treatment of HNSCC.
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影响因子：
8
作者：
McKenna, WG;Muschel, RJ;Bernhard, EJ
通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.220247197
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