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抑制甲羟戊酸途径增强 M1 病毒介导的癌细胞溶瘤作用。

Inhibition of the mevalonate pathway enhances cancer cell oncolysis mediated by M1 virus.

机构信息

Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.

Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, China.

出版信息

Nat Commun. 2018 Apr 18;9(1):1524. doi: 10.1038/s41467-018-03913-6.

DOI:10.1038/s41467-018-03913-6
PMID:29670091
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5906622/
Abstract

Oncolytic virus is an attractive anticancer agent that selectively lyses cancer through targeting cancer cells rather than normal cells. Although M1 virus is effective against several cancer types, certain cancer cells present low sensitivity to it. Here we identified that most of the components in the cholesterol biosynthesis pathway are downregulated after M1 virus infection. Further functional studies illustrate that mevalonate/protein farnesylation/ras homolog family member Q (RHOQ) axis inhibits M1 virus replication. Further transcriptome analysis shows that RHOQ knockdown obviously suppresses Rab GTPase and ATP-mediated membrane transporter system, which may mediate the antiviral effect of RHOQ. Based on this, inhibition of the above pathway significantly enhances the anticancer potency of M1 virus in vitro, in vivo, and ex vivo. Our research provides an intriguing strategy for the rational combination of M1 virus with farnesyl transferase inhibitors to enhance therapeutic efficacy.

摘要

溶瘤病毒是一种有吸引力的抗癌药物，通过靶向癌细胞而不是正常细胞选择性地裂解癌细胞。虽然 M1 病毒对几种癌症类型有效，但某些癌细胞对其敏感性较低。在这里，我们发现 M1 病毒感染后胆固醇生物合成途径中的大多数成分下调。进一步的功能研究表明，甲羟戊酸/蛋白质法呢基化/ Ras 同源家族成员 Q（RHOQ）轴抑制 M1 病毒复制。进一步的转录组分析表明，RHOQ 敲低明显抑制 Rab GTPase 和 ATP 介导的膜转运系统，这可能介导 RHOQ 的抗病毒作用。基于此，抑制上述途径可显著增强 M1 病毒在体外、体内和离体环境中的抗癌效力。我们的研究为 M1 病毒与法尼基转移酶抑制剂的合理联合提供了一种有趣的策略，以增强治疗效果。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93d2/5906622/bb4e125654cd/41467_2018_3913_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93d2/5906622/6b3b2e874eea/41467_2018_3913_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93d2/5906622/759c670b3da7/41467_2018_3913_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93d2/5906622/bd2d31059d44/41467_2018_3913_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93d2/5906622/848017e55d24/41467_2018_3913_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93d2/5906622/01cfc1ff9a08/41467_2018_3913_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93d2/5906622/bb4e125654cd/41467_2018_3913_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93d2/5906622/6b3b2e874eea/41467_2018_3913_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93d2/5906622/759c670b3da7/41467_2018_3913_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93d2/5906622/bd2d31059d44/41467_2018_3913_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93d2/5906622/848017e55d24/41467_2018_3913_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93d2/5906622/01cfc1ff9a08/41467_2018_3913_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93d2/5906622/bb4e125654cd/41467_2018_3913_Fig6_HTML.jpg

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