Active-site mTOR inhibitors augment HSV1-dICP0 infection in cancer cells via dysregulated eIF4E/4E-BP axis
| Autor: | Samuel T Workenhe, Akiko Yanagiya, Huy-Dung Hoang, Soroush Tahmasebi, Dana Pearl, Adrian Pelin, John C. Bell, Chadi Zakaria, Karen L. Mossman, Tyson E. Graber, Jaclyn Hearnden, Polen Sean, Tommy Alain, Jian-Jun Jia, Margaret Watson, Louis-Phillipe Leroux, Seyed Mehdi Jafarnejad, Jean-Simon Diallo, Nahum Sonenberg, Maritza Jaramillo, Nathaniel Robichaud, Vinh Tai Truong, Fabrice Le Boeuf |
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| Přispěvatelé: | McGill University = Université McGill [Montréal, Canada], University of Ottawa [Ottawa], Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), McMaster University [Hamilton, Ontario], Ottawa Hospital Research Institute [Ottawa] (OHRI), 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, We thank Isabelle Harvey and Lynn Kyte for technical assistance, Xu Zhang and Sebastian Morales for help with experiments, and William Muller (McGill) for the mouse mammary epithelial cells. |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cell Cycle Proteins mTORC1 Herpesvirus 1 Human MESH: Eukaryotic Initiation Factor-4E/genetics mTORC2 MESH: Immediate-Early Proteins/genetics Mice MESH: Immediate-Early Proteins/deficiency MESH: Catalytic Domain/drug effects Catalytic Domain Neoplasms MESH: Ubiquitin-Protein Ligases/genetics Chlorocebus aethiops MESH: Herpes Simplex/genetics MESH: Ubiquitin-Protein Ligases/deficiency MESH: Animals MESH: Signal Transduction/genetics Biology (General) MESH: Phosphoproteins/genetics MESH: Eukaryotic Initiation Factor-4E/metabolism Cells Cultured MESH: Phosphoproteins/metabolims MESH: TOR Serine-Threonine Kinases/chemistry TOR Serine-Threonine Kinases MESH: Neoplasms/pathology EIF4E MESH: Herpes Simplex/complications MESH: Herpes Simplex/pathology 3. Good health Gene Expression Regulation Neoplastic MESH: HEK293 Cells MESH: Cells Cultured Signal Transduction MESH: Organisms Genetically Modified QH301-705.5 Ubiquitin-Protein Ligases Immunology MESH: Gene Expression Regulation Neoplastic/drug effects MESH: Vero Cells [SDV.CAN]Life Sciences [q-bio]/Cancer MESH: Herpesvirus 1 Human/drug effects Biology MESH: Neoplasms/virology Microbiology MESH: TOR Serine-Threonine Kinases/antagonists & inhibitiors Immediate-Early Proteins MESH: Protein Kinase Inhibitors/pharmacology 03 medical and health sciences SDG 3 - Good Health and Well-being Virology Genetics medicine Animals Humans MESH: Mice Molecular Biology Protein Kinase Inhibitors Vero Cells PI3K/AKT/mTOR pathway Adaptor Proteins Signal Transducing MESH: Herpesvirus 1 Human/genetics MESH: Adaptator Proteins Signal Transducing/metabolism MESH: Humans Organisms Genetically Modified Cancer Herpes Simplex RC581-607 medicine.disease Phosphoproteins MESH: Cercopithecus aethiops MESH: Neoplasms/complications Oncolytic virus 030104 developmental biology Eukaryotic Initiation Factor-4E HEK293 Cells Viral replication Cancer cell Cancer research Parasitology Immunologic diseases. Allergy MESH: Neoplasms/genetics MESH: Adaptator Proteins Signal Transducing/genetics |
| Zdroj: | Zakaria, C, Sean, P, Hoang, H-D, Leroux, L-P, Watson, M, Workenhe, S T, Hearnden, J, Pearl, D, Truong, V T, Robichaud, N, Yanagiya, A, Tahmasebi, S, Jafarnejad, S M, Jia, J-J, Pelin, A, Diallo, J-S, Le Boeuf, F, Bell, J C, Mossman, K L, Graber, T E, Jaramillo, M, Sonenberg, N & Alain, T 2018, ' Active-site mTOR inhibitors augment HSV1-dICP0 infection in cancer cells via dysregulated eIF4E/4E-BP axis ', PLoS Pathogens, vol. 14, no. 8, e1007264 . https://doi.org/10.1371/journal.ppat.1007264 PLoS Pathogens PLoS Pathogens, Public Library of Science, 2018, 14 (8), pp.e1007264. ⟨10.1371/journal.ppat.1007264⟩ PLoS Pathogens, Vol 14, Iss 8, p e1007264 (2018) |
| ISSN: | 1553-7374 1553-7366 |
| DOI: | 10.1371/journal.ppat.1007264 |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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