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

Jiankai Liang, Li Guo, Kai Li, Xiao Xiao, Wenbo Zhu, Xiaoke Zheng, Jun Hu, Haipeng Zhang, Jing Cai, Yaya Yu, Yaqian Tan, Chuntao Li, Xincheng Liu, Cheng Hu, Ying Liu, Pengxin Qiu, Xingwen Su, Songmin He, Yuan Lin () and Guangmei Yan ()
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Jiankai Liang: Sun Yat-sen University
Li Guo: Sun Yat-sen University
Kai Li: The Sixth Affiliated Hospital of Sun Yat-sen University
Xiao Xiao: The Third Affiliated Hospital of Sun Yat-sen University
Wenbo Zhu: Sun Yat-sen University
Xiaoke Zheng: The First Affiliated Hospital of Sun Yat-sen University
Jun Hu: Sun Yat-sen University
Haipeng Zhang: Sun Yat-sen University
Jing Cai: Sun Yat-sen University
Yaya Yu: Sun Yat-sen University
Yaqian Tan: Sun Yat-sen University
Chuntao Li: Sun Yat-sen University
Xincheng Liu: Sun Yat-sen University
Cheng Hu: The Third Affiliated Hospital of Sun Yat-sen University
Ying Liu: The Third Affiliated Hospital of Sun Yat-sen University
Pengxin Qiu: Sun Yat-sen University
Xingwen Su: Sun Yat-sen University
Songmin He: Weill Cornell Medical College
Yuan Lin: Sun Yat-sen University
Guangmei Yan: Sun Yat-sen University

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03913-6

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