Inhibition of the mevalonate pathway enhances cancer cell oncolysis mediated by M1 virus.
Inhibition of the mevalonate pathway enhances cancer cell oncolysis mediated by M1 virus.
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抑制甲羟戊酸途径可增强 M1 病毒介导的癌细胞溶瘤作用
DOI：
10.1038/s41467-018-03913-6
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发表时间：
2018-04-18
影响因子：
16.6
通讯作者：
Yan G
中科院分区：
文献类型：
--
作者：
Liang J;Guo L;Li K;Xiao X;Zhu W;Zheng X;Hu J;Zhang H;Cai J;Yu Y;Tan Y;Li C;Liu X;Hu C;Liu Y;Qiu P;Su X;He S;Lin Y;Yan G
溶瘤病毒是一种有吸引力的抗癌剂，它通过靶向癌细胞而不是正常细胞选择性地溶解癌症。虽然M1病毒对几种癌症类型有效，但某些癌细胞对它的敏感性很低。在这里，我们发现在M1病毒感染后，胆固醇生物合成途径中的大多数成分都下调了。进一步的功能研究表明甲氧戊酸/蛋白法尼化/ras同源家族成员Q(RHOQ)轴抑制M1病毒的复制。进一步的转录组分析表明，RHOQ基因敲除后明显抑制Rab GTP酶和ATP介导的膜转运蛋白系统，这可能介导了RHOQ的抗病毒作用。在此基础上，抑制上述途径显著增强了M1病毒在体内外的抗癌效力。我们的研究为M1病毒与法尼基转移酶抑制剂的合理结合以提高治疗效果提供了一个有趣的策略。溶瘤病毒选择性地杀死肿瘤细胞并诱导抗肿瘤免疫。在这里，AUS展示了甲氧戊酸途径对难治性癌细胞中的溶瘤病毒M1的抗病毒作用，并为靶向甲羟戊酸途径以加强溶瘤病毒治疗的组合策略提供了证据。
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. Oncolytic viruses selectively kill tumour cells and induce anti-tumour immunity. Here, the AUs demonstrate the anti-viral effect of the mevalonate pathway on oncolytic virus M1 in refractory cancer cells and provide evidence for a combination strategy of targeting the mevalonate pathway for potentiating oncolytic virus therapy.
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DOI：
10.1146/annurev-cellbio-111315-125125
发表时间：
2016-10-06
影响因子：
11.3
作者：
Perera RM;Zoncu R
通讯作者：
Zoncu R
影响因子：
29.7
作者：
Schneider WM;Chevillotte MD;Rice CM
通讯作者：
Rice CM
影响因子：
15.9
作者：
Heaton NS;Randall G
通讯作者：
Randall G
经典的 PKA 抑制剂通过激活由 cAMP 1 直接激活的交换蛋白来增强 M1 病毒的溶瘤作用
影响因子：
--
作者：
Li K;Liang J;Lin Y;Zhang H;Xiao X;Tan Y;Cai J;Zhu W;Xing F;Hu J;Yan G
通讯作者：
Yan G
影响因子：
3.3
作者：
Inoue, M;Chiang, SH;Saltiel, AR
通讯作者：
Saltiel, AR