Li Kai, Hu Cheng, Xing Fan, Gao Mingshi, Liang Jiankai, Xiao Xiao, Cai Jing, Tan Yaqian, Hu Jun, Zhu Wenbo, Yin Wei, Li Yuan, Chen Wenli, Lu Bingzheng, Mai Jialuo, Qiu Pengxin, Su Xingwen, Yan Guangmei, Zhang Haipeng, Lin Yuan
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
J Virol. 2018 Feb 26;92(6). doi: 10.1128/JVI.01331-17. Print 2018 Mar 15.
Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancer cells. M1 is a naturally occurring alphavirus () 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 IRE1α or PERK, but not ATF6, substantially increases the oncolytic effects of the M1 virus. Moreover, inhibition of IRE1α blocks M1 virus-induced autophagy, which restricts the antitumor effects of the M1 virus through degradation of viral protein, in glioma cells. In addition, IRE1α suppression significantly increases the oncolytic effect of M1 virus in an orthotopic glioma model. From a molecular pathology study, we found that IRE1α 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. Although oncolytic virotherapy is showing great promise in clinical applications, not all patients are benefiting. Identifying inhibitory signals in refractory cancer cells for each oncolytic virus would provide a good chance to increase the therapeutic effect. Here we describe that infection with the oncolytic virus M1 triggers the unfolded protein response (UPR) and subsequent autophagy, while blocking the UPR-autophagy axis significantly potentiates the antitumor efficacy of M1 and A survey of cancer tissue banks revealed that IRE1α, a key element in the UPR pathway, is commonly downregulated in higher-grade human gliomas, suggesting favorable prospects for the application of M1. Our work provides a potential predictor and target for enhancement of the therapeutic effectiveness of the M1 virus. We predict that the mechanism-based combination therapy will promote cancer virotherapy in the future.
溶瘤病毒疗法是一种新兴的治疗方式，它利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（），对多种癌症显示出强大的溶瘤活性。病毒复制过程中未折叠蛋白的积累会导致一种称为未折叠蛋白反应（UPR）的转录/翻译反应，这可能会抵消溶瘤病毒的抗肿瘤作用。在本报告中，我们表明，对IRE1α或PERK进行药理学或生物学抑制，但不包括ATF6，可显著增强M1病毒的溶瘤作用。此外，抑制IRE1α可阻断M1病毒诱导的自噬，而自噬通过降解病毒蛋白在胶质瘤细胞中限制了M1病毒的抗肿瘤作用。此外，IRE1α抑制在原位胶质瘤模型中显著增强了M1病毒的溶瘤作用。从分子病理学研究中，我们发现IRE1α在高级别胶质瘤中表达水平较低，这表明溶瘤病毒M1具有更大的抗肿瘤疗效。综上所述，这些发现阐明了胶质瘤细胞对溶瘤病毒M1的防御机制，并确定了增强溶瘤病毒蛋白积累和随后肿瘤细胞裂解的可能方法。尽管溶瘤病毒疗法在临床应用中显示出巨大的前景，但并非所有患者都能从中受益。识别每种溶瘤病毒在难治性癌细胞中的抑制信号将为提高治疗效果提供一个很好的机会。在这里，我们描述了溶瘤病毒M1感染会触发未折叠蛋白反应（UPR）和随后的自噬，而阻断UPR-自噬轴可显著增强M1的抗肿瘤疗效，并且对癌症组织库的一项调查显示，UPR途径中的关键元件IRE1α在高级别人类胶质瘤中通常下调，这表明M1的应用前景良好。我们的工作为提高M1病毒的治疗效果提供了一个潜在的预测指标和靶点。我们预测基于机制的联合治疗将在未来促进癌症病毒疗法的发展。
