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

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

doi:10.1371/journal.ppat.1007264

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

PLoS Pathog. 2018 Aug 23;14(8):e1007264. doi: 10.1371/journal.ppat.1007264. eCollection 2018 Aug.

Authors

Chadi Zakaria¹, Polen Sean¹, Huy-Dung Hoang², Louis-Phillipe Leroux³, Margaret Watson², Samuel Tekeste Workenhe⁴, Jaclyn Hearnden¹, Dana Pearl¹, Vinh Tai Truong¹, Nathaniel Robichaud¹, Akiko Yanagiya¹, Soroush Tahmasebi¹, Seyed Mehdi Jafarnejad¹, Jian-Jun Jia², Adrian Pelin⁵, Jean-Simon Diallo⁵, Fabrice Le Boeuf⁵, John Cameron Bell⁵, Karen Louise Mossman⁴, Tyson Ernst Graber², Maritza Jaramillo³, Nahum Sonenberg¹, Tommy Alain²

Affiliations

¹ Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Canada.
² Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
³ INRS Institut Armand-Frappier Research Centre, Laval, Quebec, Canada.
⁴ Department of Pathology and Molecular Medicine, MG DeGroote Institute for Infectious Disease, McMaster University, Hamilton, Ontario, Canada.
⁵ Center for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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

Grants and funding

This research was funded by grants from the Terry Fox Research Institute to NS and TA, and the CHEO Foundation, the Cancer Research Society / Stephen E. Drabin Research Fund, the Brain Tumour Foundation of Canada, and the Canadian Breast Cancer Foundation to TA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.