Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
J Virol. 2011 Jun;85(12):6015-23. doi: 10.1128/JVI.01537-10. Epub 2011 Apr 6.
Newcastle disease virus (NDV) is a negative-sense RNA virus that has been shown to possess oncolytic activity. NDV's selective replication in tumor cells has been previously suggested to be due to the lack of a proper antiviral response in these cells. Here we demonstrate that NDV possesses oncolytic activity in tumor cells capable of a robust type I interferon (IFN) response, suggesting that another mechanism underlies NDV's tumor specificity. We show that the oncolytic selectivity of NDV for tumor cells is dependent upon tumor cell resistance to apoptosis. Utilizing the human non-small-cell lung cancer cell line A549 overexpressing the antiapoptotic protein Bcl-xL, we show significant enhancement of oncolytic activity and NDV replication. Interestingly, while the Bcl-xL-overexpressing cells were resistant to apoptotic stimuli induced by chemotherapeutic agents and early viral replication, during the subsequent viral cycles, we observed a paradoxical increase in apoptosis in response to NDV. The increased oncolytic activity seen was secondary to enhanced viral replication and syncytium formation. The induction of a type I IFN response was enhanced in Bcl-xL cells. Overall, these findings propose a new mechanism for cancer cell specificity for NDV, making it an attractive anticancer agent for chemoresistant tumors with enhanced antiapoptotic activity.
新城疫病毒（NDV）是一种负义 RNA 病毒，已被证明具有溶瘤活性。NDV 选择性地在肿瘤细胞中复制，以前被认为是由于这些细胞中缺乏适当的抗病毒反应。在这里，我们证明 NDV 在能够产生强烈的 I 型干扰素（IFN）反应的肿瘤细胞中具有溶瘤活性，这表明 NDV 的肿瘤特异性还有另一种机制。我们表明，NDV 对肿瘤细胞的溶瘤选择性取决于肿瘤细胞对细胞凋亡的抵抗能力。利用过表达抗凋亡蛋白 Bcl-xL 的人非小细胞肺癌细胞系 A549，我们显示出明显增强的溶瘤活性和 NDV 复制。有趣的是，虽然 Bcl-xL 过表达细胞对化疗药物和早期病毒复制诱导的凋亡刺激具有抗性，但在随后的病毒周期中，我们观察到对 NDV 的凋亡反应呈反式增加。观察到的增加的溶瘤活性是由于病毒复制和合胞体形成增强所致。Bcl-xL 细胞中诱导的 I 型 IFN 反应增强。总的来说，这些发现为 NDV 对癌细胞的特异性提出了一种新的机制，使其成为具有增强的抗凋亡活性的化疗耐药肿瘤的有吸引力的抗癌药物。
