溶瘤新城疫病毒通过自噬效应杀伤耐药肺癌细胞的分子机制及应用

Drugresistance represents an important cause of chemotherapy failure in clinical treatment of lung cancer. We previously showed that oncolytic Newcastle disease virus (NDV) lyses the cisplatin-resistant lung cancer cells （Cancer Letter, 2012）, however, its oncolytic effect needs to be enhanced. We recently demonstrated that autophagy may be involved in NDV-mediated oncolysis (Arch Virol, 2012). Our preliminary data indicated that NDV triggers autophagy in infected drug-resistant lung cancer A549 cells, suggesting that autophagy modulation may enhance NDV-mediated oncolytic effect. This project will elucidate the molecular and cellular mechanism by which NDV induces autophagy in drug-resistant lung cancer cells through investigating the role of autophagy-related genes Beclin-1 and Atg5, signaling pathways regulating autophagy such as class I PI3K/Akt/mTOR, class III PI3K/Beclin-1, MAPK and ER stress, as well as the differential expression of genes involved in autophagy machinery formation and regulating autophagy. In addition, autophagy modulators will be tested to increase NDV-induced oncolytic effect on drug-resistant lung cancer cells both in vitro and in vivo, providing the basis for the clinical treatment of drug-reistant luncacer by NDV.

耐药抵抗是临床肺癌化疗失败的重要原因。申请人前期研究显示，溶瘤新城疫病毒(Newcastle disease virus, NDV)杀伤耐药肺癌细胞 （Cancer letter, 2012），但其溶瘤性能有待提高。申请人的近期研究表明自噬可能与NDV溶瘤相关(Arch virol, 2012)，预实验证实NDV感染耐药肺癌细胞引发自噬，提示调控自噬可能增强NDV的溶瘤性能。申请人拟通过对自噬关键蛋白Beclin-1和Atg5以及自噬调节通路I型PI3K/Akt/mTOR、III型PI3K/Beclin-1、MAPK通路及内质网应激等的研究，并分析自噬组成基因和自噬调节基因的差异表达，阐明NDV引起耐药肺癌细胞自噬的分子细胞机制。此外，通过研究调控自噬对NDV体内外溶瘤效应的作用及机制，筛选适用于不同耐药肺癌的自噬调节剂，为临床提高NDV对耐药肺癌的溶瘤性能和耐药肺癌的个体化治疗提供依据。

溶瘤新城疫病毒（Newcastle disease virus，NDV），一种禽类副粘病毒，可在多种肿瘤中复制，并具有强的细胞毒性杀伤力,是一种很有前途的治疗癌症的药物抵抗。然而，低疗效使其临床应用受到限制。我们研究表明：1. 新城疫病毒FMW毒株诱导耐紫杉醇肺癌细胞自噬，抑制耐顺铂肺癌细胞自噬；2. 新城疫病毒通过PI3K/AKT通路调控自噬发生；3. 调控自噬促进新城疫病毒的溶瘤能力；4. 新城疫病毒通过自噬途径诱导肺癌干细胞死亡。本课题为NDV有效地用于肿瘤的溶瘤病毒治疗，临床提高NDV对耐药肺癌的溶瘤性能和耐药肺癌的个体化治疗提供依据。本课题共发表SCI论文7篇，课题负责人孟松树获得辽宁省科学技术进步二等奖1项、培养研究生3名，其中博士1名，硕士2名。