Deficiency of the IRE1α-Autophagy Axis Enhances the Antitumor Effects of the Oncolytic Virus M1
Deficiency of the IRE1α-Autophagy Axis Enhances the Antitumor Effects of the Oncolytic Virus M1
复制标题
IRE1α-自噬轴的缺陷增强了溶瘤病毒 M1 的抗肿瘤作用
作者：
Kai Li;Cheng Hu;Fan Xing;Mingshi Gao;Jiankai Liang;Xiao Xiao;Jing Cai;Yaqian Tan;Jun Hu;Wenbo Zhu;Wei Yin;Yuan Li;Wenli Chen;Bingzheng Lu;Jialuo Mai;Pengxin Qiu;Xingwen Su;Guangmei Yan;Haipeng Zhang;Yuan Lin
溶瘤病毒疗法是一种新兴的治疗方式，其使用具有复制能力的病毒来破坏癌细胞。M1是一种天然存在的甲病毒（披膜病毒科），对许多癌症显示出有效的溶瘤活性。病毒复制期间未折叠蛋白的积累导致称为未折叠蛋白应答（UPR）的转录/翻译应答，其可能抵消溶瘤病毒的抗肿瘤作用。在这份报告中，我们表明，无论是药理学或生物学抑制IRE 1或PERK，而不是ATF 6，大大增加了M1病毒的溶瘤作用。此外，IRE 1的抑制阻断了M1病毒诱导的自噬，这限制了M1病毒通过降解病毒蛋白在神经胶质瘤细胞中的抗肿瘤作用。此外，IRE 1抑制显著增加了原位神经胶质瘤模型中M1病毒的溶瘤作用。从分子病理学研究中，我们发现IRE 1在高级别胶质瘤中的水平较低，表明溶瘤病毒M1的抗肿瘤功效更大。expressed.at总之，这些发现说明了一种防御机制。胶质瘤细胞对溶瘤病毒M1和识别可能的方法。增强溶瘤病毒蛋白的积累和随后的溶解肿瘤细胞。
Oncolytic virotherapy is an emerging treatment modality that uses.replication-competent viruses to destroy cancer cells. M1 is a naturally occurring alphavirus (Togaviridae) which shows potent oncolytic activities against many cancers..Accumulation of unfolded proteins during virus replication leads to a transcriptional/.translational response known as the unfolded protein response (UPR), which might.counteract the antitumor effect of the oncolytic virus. In this report, we show that.either pharmacological or biological inhibition of IRE1 or PERK, but not ATF6, substantially increases the oncolytic effects of the M1 virus. Moreover, inhibition of.IRE1 blocks M1 virus-induced autophagy, which restricts the antitumor effects of.the M1 virus through degradation of viral protein, in glioma cells. In addition, IRE1.suppression significantly increases the oncolytic effect of M1 virus in an orthotopic.glioma model. From a molecular pathology study, we found that IRE1 is expressed.at lower levels in higher-grade gliomas, suggesting greater antitumor efficacy of the.oncolytic virus M1. Taken together, these findings illustrate a defensive mechanism.of glioma cells against the oncolytic virus M1 and identify possible approaches to.enhance the oncolytic viral protein accumulation and the subsequent lysis of tumor.cells.