[Synergistic Effect of NF-κB Signaling Pathway Inhibitor and Oncolytic Measles Virus Vaccine Strain against Lung Cancer and Underlying Mechanisms]

Lung cancer is one of the leading causes of cancer-related morbidity and mortality. Oncolytic virotherapy is an emerging therapeutic modality that utilizes replication-competent viruses to destroy cancers. As a powerful tool to kill tumor cells with excellent safety profile, attenuated measles virus of the Edmonston strain (MV-Edm) has been widely applied in the development of tumor therapy and preclinical trials. The

The combination of NF-κB signaling pathway inhibitor pS1145 and oncolytic measles virus vaccine strains can promote the apoptosis of human lung cancer cells A549 and H1299 and enhance their oncolytic effect. 【中文题目：NF-κB信号通路抑制剂与溶瘤麻疹病毒 疫苗株协同抗肺癌的作用及机制】 【中文摘要：背景与目的 肺癌已成为我国发病率和死亡率居首位的恶性肿瘤。能自我复制、选择性杀伤肿瘤的溶瘤病毒，是治疗恶性肿瘤的有效策略，而其中溶瘤麻疹病毒疫苗株因其良好的溶瘤效果，且对正常细胞无损伤或微损伤，已进入几项临床试验。本研究旨在探讨核转录因子κB（nuclear factor kappa B, NF-κB）信号通路抑制剂与溶瘤麻疹病毒疫苗株协同抗肺癌的作用及机制。方法 应用Western blot方法检测MV-Edm感染人肺癌细胞A549和H1299并应用细胞自噬相关的siRNA或者应用NF-кB通路抑制剂PS1145后SQSTM1、p-IκBα、IκBα、PARP及BAX的表达水平，运用流式细胞术分析各组细胞凋亡率的变化，同时采用噻唑蓝［3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide, MTT］法检测各组细胞的存活率。结果 Western blot结果显示MV-Edm感染人肺癌细胞A549和H1299后，自噬引起NF-κB通路的激活，进而抑制细胞凋亡。抑制细胞自噬可抑制NF-κB通路的激活，MV-Edm感染后p-IκBα表达水平随着感染时间有不同程度的升高，IκBα的表达水平则降低，NF-κB通路抑制剂PS1145可促进人肺癌细胞A549和H1299凋亡（P<0.01），并增强其溶瘤效果。结论 NF-κB信号通路抑制剂PS1145与溶瘤麻疹病毒疫苗株联合可促进人肺癌细胞A549和H1299凋亡，并增强其溶瘤效果。 】 【中文关键词：溶瘤麻疹病毒疫苗株；细胞自噬；NF-κB通路；细胞凋亡】.

Using Western blot to detect MV-Edm infection of A549 and H1299 were infected by MV-Edm alone or used the NF-κB pathway inhibitor PS1145/cell autophagy related siRNA, expression level of p-IκBα, IκBα, PARP and BAX were determined by western blot. Using flow cytometry to analysis the rate of apoptosis, and using MTT [3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide] method to detect the cell survival rate.

Inhibition of cell autophagy could obviously inhibit the MV-Edm infection induced the NF-κB pathway activation in A549 and H1299. In MV-Edm infected A549 and H1299, p-IκBα level increased and IκBα level decreased over infection time, compared with control group. Inhibition of the NF-κB pathway by PS1145 could promote the apoptosis of MV-Edm infected A549 and H1299 and amplify the tumor killing effect. Conclusions: The combination of NF-κB signaling pathway inhibitor pS1145 and oncolytic measles virus vaccine strains can promote the apoptosis of human lung cancer cells A549 and H1299 and enhance their oncolytic effect. 【中文题目：NF-κB信号通路抑制剂与溶瘤麻疹病毒 疫苗株协同抗肺癌的作用及机制】 【中文摘要：背景与目的 肺癌已成为我国发病率和死亡率居首位的恶性肿瘤。能自我复制、选择性杀伤肿瘤的溶瘤病毒，是治疗恶性肿瘤的有效策略，而其中溶瘤麻疹病毒疫苗株因其良好的溶瘤效果，且对正常细胞无损伤或微损伤，已进入几项临床试验。本研究旨在探讨核转录因子κB（nuclear factor kappa B, NF-κB）信号通路抑制剂与溶瘤麻疹病毒疫苗株协同抗肺癌的作用及机制。方法 应用Western blot方法检测MV-Edm感染人肺癌细胞A549和H1299并应用细胞自噬相关的siRNA或者应用NF-кB通路抑制剂PS1145后SQSTM1、p-IκBα、IκBα、PARP及BAX的表达水平，运用流式细胞术分析各组细胞凋亡率的变化，同时采用噻唑蓝［3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide, MTT］法检测各组细胞的存活率。结果 Western blot结果显示MV-Edm感染人肺癌细胞A549和H1299后，自噬引起NF-κB通路的激活，进而抑制细胞凋亡。抑制细胞自噬可抑制NF-κB通路的激活，MV-Edm感染后p-IκBα表达水平随着感染时间有不同程度的升高，IκBα的表达水平则降低，NF-κB通路抑制剂PS1145可促进人肺癌细胞A549和H1299凋亡（P<0.01），并增强其溶瘤效果。结论 NF-κB信号通路抑制剂PS1145与溶瘤麻疹病毒疫苗株联合可促进人肺癌细胞A549和H1299凋亡，并增强其溶瘤效果。 】 【中文关键词：溶瘤麻疹病毒疫苗株；细胞自噬；NF-κB通路；细胞凋亡】.