Active-site mTOR inhibitors augment HSV1-dICP0 infection in cancer cells via dysregulated eIF4E/4E-BP axis.

Abstract

Herpes Simplex Virus 1 (HSV1) is amongst the most clinically advanced oncolytic virus platforms. However, efficient and sustained viral replication within tumours is limiting. Rapamycin can stimulate HSV1 replication in cancer cells, but active-site dual mTORC1 and mTORC2 (mammalian target of rapamycin complex 1 and 2) inhibitors (asTORi) were shown to suppress the virus in normal cells. Surprisingly, using the infected cell protein 0 (ICP0)-deleted HSV1 (HSV1-dICP0), we found that asTORi markedly augment infection in cancer cells and a mouse mammary cancer xenograft. Mechanistically, asTORi repressed mRNA translation in normal cells, resulting in defective antiviral response but also inhibition of HSV1-dICP0 replication. asTORi also reduced antiviral response in cancer cells, however in contrast to normal cells, transformed cells and cells transduced to elevate the expression of eukaryotic initiation factor 4E (eIF4E) or to silence the repressors eIF4E binding proteins (4E-BPs), selectively maintained HSV1-dICP0 protein synthesis during asTORi treatment, ultimately supporting increased viral replication. Our data show that altered eIF4E/4E-BPs expression can act to promote HSV1-dICP0 infection under prolonged mTOR inhibition. Thus, pharmacoviral combination of asTORi and HSV1 can target cancer cells displaying dysregulated eIF4E/4E-BPs axis.

• Authors: Chadi Zakaria, Polen Sean, Huy-Dung Hoang, Louis-Phillipe Leroux, Margaret Watson, Samuel Tekeste Workenhe, Jaclyn Hearnden, Dana Pearl, Vinh Tai Truong, Nathaniel Robichaud, Akiko Yanagiya, Soroush Tahmasebi, Seyed Mehdi Jafarnejad, Jian-Jun Jia, Adrian Pelin, Jean-Simon Diallo, Fabrice Le Boeuf, John Cameron Bell, Karen Louise Mossman, Tyson Ernst Graber, Maritza Jaramillo, Nahum Sonenberg, Tommy Alain
• Journal: PLoS pathogens (PLoS Pathog) Vol. 14 Issue 8 Pg. e1007264 (08 2018) ISSN: 1553-7374 [Electronic] United States
• PMID: 30138450 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Cell Cycle Proteins
• EIF4EBP1 protein, human
• Eukaryotic Initiation Factor-4E
• Immediate-Early Proteins
• Phosphoproteins
• Protein Kinase Inhibitors
• Ubiquitin-Protein Ligases
• Vmw110 protein, Human herpesvirus 1
• TOR Serine-Threonine Kinases

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Animals
• Catalytic Domain (drug effects)
• Cell Cycle Proteins
• Cells, Cultured
• Chlorocebus aethiops
• Eukaryotic Initiation Factor-4E (genetics, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• HEK293 Cells
• Herpes Simplex (complications, genetics, pathology)
• Herpesvirus 1, Human (drug effects, genetics)
• Humans
• Immediate-Early Proteins (deficiency, genetics)
• Mice
• Neoplasms (complications, genetics, pathology, virology)
• Organisms, Genetically Modified
• Phosphoproteins (genetics, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Signal Transduction (genetics)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, chemistry)
• Ubiquitin-Protein Ligases (deficiency, genetics)
• Vero Cells