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靶向抑制 GRP78 可通过内质网应激和自噬促进肺癌细胞凋亡。

Targeted inhibition of GRP78 by HA15 promotes apoptosis of lung cancer cells accompanied by ER stress and autophagy.

机构信息

Center for Lipid Research, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing 400016, P.R. China.

Department of Nutrition and Food Hygiene, School of Public Health and Management, Chongqing Medical University, Chongqing 400016, P.R. China.

出版信息

Biol Open. 2020 Nov 12;9(11):bio053298. doi: 10.1242/bio.053298.

DOI:10.1242/bio.053298
PMID:33115703
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7673357/
Abstract

This study investigated the pathophysiological role of GRP78 in the survival of lung cancer cells. Lung cancer patient data from public databases were used to analyze the expression of GRP78 and its influence on prognoses. , GRP78 protein expression was analyzed in an established urethane-induced lung tumor mouse model. , the effects of targeted inhibition of GRP78 by HA15 in lung cancer cells were assessed, with cell viability analyzed using a CCK-8 assay, cell proliferation using an EdU assay, apoptosis and cell cycle using flow cytometry, subcellular structure using electron microscopy, and relative mRNA and protein expression using RT-PCR, western blotting or immunofluorescence assays. The results showed that GRP78 was highly expressed in the lung tissue of lung cancer mice model or patients, and was associated with a poor prognosis. After inhibition of GRP78 in lung cancer cells by HA15, cell viability was decreased in a dose- and time-dependent manner, proliferation was suppressed and apoptosis promoted. Unfolded protein response signaling pathway proteins were activated, and the autophagy-related proteins and mRNAs were upregulated. Therefore, targeted inhibition of GRP78 by HA15 promotes apoptosis of lung cancer cells accompanied by ER stress and autophagy.

摘要

本研究探讨了 GRP78 在肺癌细胞存活中的病理生理学作用。利用公共数据库中的肺癌患者数据，分析了 GRP78 的表达及其对预后的影响。在建立的乌氨酸诱导的肺癌肿瘤小鼠模型中分析了 GRP78 蛋白表达。评估了靶向抑制 GRP78 的 HA15 对肺癌细胞的作用，使用 CCK-8 测定法分析细胞活力，使用 EdU 测定法分析细胞增殖，使用流式细胞术分析细胞凋亡和细胞周期，使用电子显微镜观察亚细胞结构，使用 RT-PCR、western blot 或免疫荧光测定法分析相对 mRNA 和蛋白质表达。结果表明，GRP78 在肺癌小鼠模型或患者的肺组织中高表达，与预后不良相关。用 HA15 抑制肺癌细胞中的 GRP78 后，细胞活力呈剂量和时间依赖性降低，增殖受到抑制，凋亡增加。未折叠蛋白反应信号通路蛋白被激活，自噬相关蛋白和 mRNAs 上调。因此，HA15 靶向抑制 GRP78 可促进肺癌细胞凋亡，伴有内质网应激和自噬。

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