Active-site mTOR inhibitors augment HSV1-dICP0 infection in cancer cells via dysregulated eIF4E/4E-BP axis
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 rapamy...
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| Veröffentlicht in: | PLoS pathogens 2018-08, Vol.14 (8), p.e1007264-e1007264 |
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| creator | Zakaria, Chadi Sean, Polen Hoang, Huy-Dung Leroux, Louis-Phillipe Watson, Margaret Workenhe, Samuel Tekeste Hearnden, Jaclyn Pearl, Dana Truong, Vinh Tai Robichaud, Nathaniel Yanagiya, Akiko Tahmasebi, Soroush Jafarnejad, Seyed Mehdi Jia, Jian-Jun Pelin, Adrian Diallo, Jean-Simon Le Boeuf, Fabrice Bell, John Cameron Mossman, Karen Louise Graber, Tyson Ernst Jaramillo, Maritza Sonenberg, Nahum Alain, Tommy |
| description | 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. |
| doi_str_mv | 10.1371/journal.ppat.1007264 |
| format | Article |
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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.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1007264</identifier><identifier>PMID: 30138450</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adaptator Proteins, Signal Transducing/genetics ; Adaptator Proteins, Signal Transducing/metabolism ; Adaptor Proteins, Signal Transducing - genetics ; Adaptor Proteins, Signal Transducing - metabolism ; Animals ; Biochemistry ; Biology and life sciences ; Breast cancer ; Cancer ; Cancer cells ; Catalytic Domain - drug effects ; Cells, Cultured ; Cercopithecus aethiops ; Children & youth ; Eukaryotic Initiation Factor-4E - genetics ; Eukaryotic Initiation Factor-4E - metabolism ; Funding ; Gene Expression Regulation, Neoplastic - drug effects ; Genetic aspects ; Genetic regulation ; Genomes ; HEK293 Cells ; Herpes simplex ; Herpes Simplex - complications ; Herpes Simplex - genetics ; Herpes Simplex - pathology ; Herpes simplex virus ; Herpes viruses ; Herpesvirus 1, Human - drug effects ; Herpesvirus 1, Human - genetics ; Humans ; Immediate-Early Proteins - deficiency ; Immediate-Early Proteins - genetics ; Immunology ; Immunotherapy ; Infections ; Infectious diseases ; Inhibition ; Inhibitors ; Initiation factor eIF-4E ; Kinases ; Life Sciences ; Medical research ; Medicine and Health Sciences ; Mice ; mRNA ; Neoplasms - complications ; Neoplasms - genetics ; Neoplasms - pathology ; Neoplasms - virology ; Oncolysis ; Organisms, Genetically Modified ; Pharmacology ; Phosphoproteins - genetics ; Phosphoproteins - metabolism ; Phosphoproteins/metabolims ; Physiological aspects ; Protein biosynthesis ; Protein Kinase Inhibitors - pharmacology ; Protein synthesis ; Proteins ; Rapamycin ; Replication ; Repressors ; Research and Analysis Methods ; Signal Transduction - genetics ; Supervision ; TOR protein ; TOR Serine-Threonine Kinases - antagonists & inhibitors ; TOR Serine-Threonine Kinases - chemistry ; TOR Serine-Threonine Kinases/antagonists & inhibitiors ; Transformed cells ; Transplants & implants ; Tumors ; Ubiquitin-Protein Ligases - deficiency ; Ubiquitin-Protein Ligases - genetics ; Vero Cells ; Viruses ; Xenografts ; Xenotransplantation</subject><ispartof>PLoS pathogens, 2018-08, Vol.14 (8), p.e1007264-e1007264</ispartof><rights>COPYRIGHT 2018 Public Library of Science</rights><rights>2018 Zakaria et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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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.</description><subject>Adaptator Proteins, Signal Transducing/genetics</subject><subject>Adaptator Proteins, Signal Transducing/metabolism</subject><subject>Adaptor Proteins, Signal Transducing - genetics</subject><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Animals</subject><subject>Biochemistry</subject><subject>Biology and life sciences</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cancer cells</subject><subject>Catalytic Domain - drug effects</subject><subject>Cells, Cultured</subject><subject>Cercopithecus aethiops</subject><subject>Children & youth</subject><subject>Eukaryotic Initiation Factor-4E - genetics</subject><subject>Eukaryotic Initiation Factor-4E - metabolism</subject><subject>Funding</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Genetic aspects</subject><subject>Genetic regulation</subject><subject>Genomes</subject><subject>HEK293 Cells</subject><subject>Herpes simplex</subject><subject>Herpes Simplex - complications</subject><subject>Herpes Simplex - genetics</subject><subject>Herpes Simplex - pathology</subject><subject>Herpes simplex virus</subject><subject>Herpes viruses</subject><subject>Herpesvirus 1, Human - drug effects</subject><subject>Herpesvirus 1, Human - genetics</subject><subject>Humans</subject><subject>Immediate-Early Proteins - deficiency</subject><subject>Immediate-Early Proteins - genetics</subject><subject>Immunology</subject><subject>Immunotherapy</subject><subject>Infections</subject><subject>Infectious diseases</subject><subject>Inhibition</subject><subject>Inhibitors</subject><subject>Initiation factor eIF-4E</subject><subject>Kinases</subject><subject>Life Sciences</subject><subject>Medical research</subject><subject>Medicine and Health Sciences</subject><subject>Mice</subject><subject>mRNA</subject><subject>Neoplasms - complications</subject><subject>Neoplasms - genetics</subject><subject>Neoplasms - pathology</subject><subject>Neoplasms - virology</subject><subject>Oncolysis</subject><subject>Organisms, Genetically Modified</subject><subject>Pharmacology</subject><subject>Phosphoproteins - genetics</subject><subject>Phosphoproteins - metabolism</subject><subject>Phosphoproteins/metabolims</subject><subject>Physiological aspects</subject><subject>Protein biosynthesis</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein synthesis</subject><subject>Proteins</subject><subject>Rapamycin</subject><subject>Replication</subject><subject>Repressors</subject><subject>Research and Analysis Methods</subject><subject>Signal Transduction - genetics</subject><subject>Supervision</subject><subject>TOR protein</subject><subject>TOR Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>TOR Serine-Threonine Kinases - chemistry</subject><subject>TOR Serine-Threonine Kinases/antagonists & inhibitiors</subject><subject>Transformed cells</subject><subject>Transplants & implants</subject><subject>Tumors</subject><subject>Ubiquitin-Protein Ligases - deficiency</subject><subject>Ubiquitin-Protein Ligases - genetics</subject><subject>Vero Cells</subject><subject>Viruses</subject><subject>Xenografts</subject><subject>Xenotransplantation</subject><issn>1553-7374</issn><issn>1553-7366</issn><issn>1553-7374</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqVk11v0zAUhiMEYmPwDxBE4gYu0vkzdm4mlaqjlSo2bYNby7GdzFUSl9iptn-PS7NpnXaDfGHLft7XPuf4JMlHCCYQM3i6dkPfyWay2cgwgQAwlJNXyTGkFGcMM_L6yfooeef9GgACMczfJkcYQMwJBcfJeqqC3ZrM22DS9ubiKrXdrS1tcL1P5VC3pgvp4vo3zPRydgniaWWiwnVxlSrZKdOnyjSNT7dWpvre96YeGhmMTs3ynMxPyTz7fpnKO-vfJ28q2XjzYZxPkl_n85vZIltd_FjOpqtM5UURMo0KCWlFGAdca1RqwKEyvOS6KjVXGuVFzitEIaCsZKgAFVKwACXEpKSIM3ySfN77bhrnxZgmL9BOwilgeSSWe0I7uRab3rayvxdOWvFvw_W1kH2wqjGCQiwpJWWuiCYU68JwVFU5pkwBaCoVvc7G24ayNVrFfPWyOTA9POnsrajdVuQQEQ5JNMj2BrfPZIvpSmykD2boBUAQ5wizLYz81_HC3v0ZjA-itX5XAtkZN8Q4QYExZDkDEf3yDH05GyNVyxhwLLCL71Q7UzGllHFWMF5EavICFYc2rVWuM5WN-weCbweCyARzF2o5eC-W11f_wf48ZMmeVb3z8btVj0mDQOw64yFIsesMMXZGlH16WqdH0UMr4L-v8waW</recordid><startdate>20180823</startdate><enddate>20180823</enddate><creator>Zakaria, 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mTOR inhibitors augment HSV1-dICP0 infection in cancer cells via dysregulated eIF4E/4E-BP axis</title><author>Zakaria, Chadi ; Sean, Polen ; Hoang, Huy-Dung ; Leroux, Louis-Phillipe ; Watson, Margaret ; Workenhe, Samuel Tekeste ; Hearnden, Jaclyn ; Pearl, Dana ; Truong, Vinh Tai ; Robichaud, Nathaniel ; Yanagiya, Akiko ; Tahmasebi, Soroush ; Jafarnejad, Seyed Mehdi ; Jia, Jian-Jun ; Pelin, Adrian ; Diallo, Jean-Simon ; Le Boeuf, Fabrice ; Bell, John Cameron ; Mossman, Karen Louise ; Graber, Tyson Ernst ; Jaramillo, Maritza ; Sonenberg, Nahum ; Alain, Tommy</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c699t-d29a15f47808dd2bd081ce8b8dfbd8cd26968f251057b7290f2c190b134b52873</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adaptator Proteins, Signal Transducing/genetics</topic><topic>Adaptator Proteins, Signal Transducing/metabolism</topic><topic>Adaptor Proteins, Signal Transducing - genetics</topic><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Animals</topic><topic>Biochemistry</topic><topic>Biology and life sciences</topic><topic>Breast cancer</topic><topic>Cancer</topic><topic>Cancer cells</topic><topic>Catalytic Domain - drug effects</topic><topic>Cells, Cultured</topic><topic>Cercopithecus aethiops</topic><topic>Children & youth</topic><topic>Eukaryotic Initiation Factor-4E - genetics</topic><topic>Eukaryotic Initiation Factor-4E - metabolism</topic><topic>Funding</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Genetic aspects</topic><topic>Genetic regulation</topic><topic>Genomes</topic><topic>HEK293 Cells</topic><topic>Herpes simplex</topic><topic>Herpes Simplex - complications</topic><topic>Herpes Simplex - genetics</topic><topic>Herpes Simplex - pathology</topic><topic>Herpes simplex virus</topic><topic>Herpes viruses</topic><topic>Herpesvirus 1, Human - drug 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Kinase Inhibitors - pharmacology</topic><topic>Protein synthesis</topic><topic>Proteins</topic><topic>Rapamycin</topic><topic>Replication</topic><topic>Repressors</topic><topic>Research and Analysis Methods</topic><topic>Signal Transduction - genetics</topic><topic>Supervision</topic><topic>TOR protein</topic><topic>TOR Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>TOR Serine-Threonine Kinases - chemistry</topic><topic>TOR Serine-Threonine Kinases/antagonists & inhibitiors</topic><topic>Transformed cells</topic><topic>Transplants & implants</topic><topic>Tumors</topic><topic>Ubiquitin-Protein Ligases - deficiency</topic><topic>Ubiquitin-Protein Ligases - genetics</topic><topic>Vero Cells</topic><topic>Viruses</topic><topic>Xenografts</topic><topic>Xenotransplantation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zakaria, Chadi</creatorcontrib><creatorcontrib>Sean, Polen</creatorcontrib><creatorcontrib>Hoang, Huy-Dung</creatorcontrib><creatorcontrib>Leroux, Louis-Phillipe</creatorcontrib><creatorcontrib>Watson, Margaret</creatorcontrib><creatorcontrib>Workenhe, Samuel Tekeste</creatorcontrib><creatorcontrib>Hearnden, Jaclyn</creatorcontrib><creatorcontrib>Pearl, Dana</creatorcontrib><creatorcontrib>Truong, Vinh Tai</creatorcontrib><creatorcontrib>Robichaud, Nathaniel</creatorcontrib><creatorcontrib>Yanagiya, Akiko</creatorcontrib><creatorcontrib>Tahmasebi, Soroush</creatorcontrib><creatorcontrib>Jafarnejad, Seyed Mehdi</creatorcontrib><creatorcontrib>Jia, Jian-Jun</creatorcontrib><creatorcontrib>Pelin, Adrian</creatorcontrib><creatorcontrib>Diallo, Jean-Simon</creatorcontrib><creatorcontrib>Le Boeuf, Fabrice</creatorcontrib><creatorcontrib>Bell, John Cameron</creatorcontrib><creatorcontrib>Mossman, Karen Louise</creatorcontrib><creatorcontrib>Graber, Tyson Ernst</creatorcontrib><creatorcontrib>Jaramillo, Maritza</creatorcontrib><creatorcontrib>Sonenberg, Nahum</creatorcontrib><creatorcontrib>Alain, Tommy</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS pathogens</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zakaria, Chadi</au><au>Sean, Polen</au><au>Hoang, Huy-Dung</au><au>Leroux, Louis-Phillipe</au><au>Watson, Margaret</au><au>Workenhe, Samuel Tekeste</au><au>Hearnden, Jaclyn</au><au>Pearl, Dana</au><au>Truong, Vinh Tai</au><au>Robichaud, Nathaniel</au><au>Yanagiya, Akiko</au><au>Tahmasebi, Soroush</au><au>Jafarnejad, Seyed Mehdi</au><au>Jia, Jian-Jun</au><au>Pelin, Adrian</au><au>Diallo, Jean-Simon</au><au>Le Boeuf, Fabrice</au><au>Bell, John Cameron</au><au>Mossman, Karen Louise</au><au>Graber, Tyson Ernst</au><au>Jaramillo, Maritza</au><au>Sonenberg, Nahum</au><au>Alain, Tommy</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Active-site mTOR inhibitors augment HSV1-dICP0 infection in cancer cells via dysregulated eIF4E/4E-BP axis</atitle><jtitle>PLoS pathogens</jtitle><addtitle>PLoS Pathog</addtitle><date>2018-08-23</date><risdate>2018</risdate><volume>14</volume><issue>8</issue><spage>e1007264</spage><epage>e1007264</epage><pages>e1007264-e1007264</pages><issn>1553-7374</issn><issn>1553-7366</issn><eissn>1553-7374</eissn><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>30138450</pmid><doi>10.1371/journal.ppat.1007264</doi><orcidid>https://orcid.org/0000-0002-4862-2795</orcidid><orcidid>https://orcid.org/0000-0002-1725-5873</orcidid><orcidid>https://orcid.org/0000-0003-3706-2304</orcidid><orcidid>https://orcid.org/0000-0002-9736-1827</orcidid><orcidid>https://orcid.org/0000-0002-5337-3404</orcidid><orcidid>https://orcid.org/0000-0002-7653-0767</orcidid><orcidid>https://orcid.org/0000-0002-0396-9138</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1553-7374 |
| ispartof | PLoS pathogens, 2018-08, Vol.14 (8), p.e1007264-e1007264 |
| issn | 1553-7374 1553-7366 1553-7374 |
| language | eng |
| recordid | cdi_plos_journals_2251085076 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; PubMed Central Open Access; Public Library of Science (PLoS) |
| subjects | Adaptator Proteins, Signal Transducing/genetics Adaptator Proteins, Signal Transducing/metabolism Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Animals Biochemistry Biology and life sciences Breast cancer Cancer Cancer cells Catalytic Domain - drug effects Cells, Cultured Cercopithecus aethiops Children & youth Eukaryotic Initiation Factor-4E - genetics Eukaryotic Initiation Factor-4E - metabolism Funding Gene Expression Regulation, Neoplastic - drug effects Genetic aspects Genetic regulation Genomes HEK293 Cells Herpes simplex Herpes Simplex - complications Herpes Simplex - genetics Herpes Simplex - pathology Herpes simplex virus Herpes viruses Herpesvirus 1, Human - drug effects Herpesvirus 1, Human - genetics Humans Immediate-Early Proteins - deficiency Immediate-Early Proteins - genetics Immunology Immunotherapy Infections Infectious diseases Inhibition Inhibitors Initiation factor eIF-4E Kinases Life Sciences Medical research Medicine and Health Sciences Mice mRNA Neoplasms - complications Neoplasms - genetics Neoplasms - pathology Neoplasms - virology Oncolysis Organisms, Genetically Modified Pharmacology Phosphoproteins - genetics Phosphoproteins - metabolism Phosphoproteins/metabolims Physiological aspects Protein biosynthesis Protein Kinase Inhibitors - pharmacology Protein synthesis Proteins Rapamycin Replication Repressors Research and Analysis Methods Signal Transduction - genetics Supervision TOR protein TOR Serine-Threonine Kinases - antagonists & inhibitors TOR Serine-Threonine Kinases - chemistry TOR Serine-Threonine Kinases/antagonists & inhibitiors Transformed cells Transplants & implants Tumors Ubiquitin-Protein Ligases - deficiency Ubiquitin-Protein Ligases - genetics Vero Cells Viruses Xenografts Xenotransplantation |
| title | Active-site mTOR inhibitors augment HSV1-dICP0 infection in cancer cells via dysregulated eIF4E/4E-BP axis |
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