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Utilizing Ras Signaling Pathway to Direct Selective Replication of Herpes Simplex Virus-1

Re-engineering the tropism of viruses is an attractive translational strategy for targeting cancer cells. The Ras signal transduction pathway is a central hub for a variety of pro-oncogenic events with a fundamental role in normal and neoplastic physiology. In this work we were interested in linking...

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Autores principales: Pan, Weihong, Bodempudi, Vidya, Esfandyari, Tuba, Farassati, Faris
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715884/
https://www.ncbi.nlm.nih.gov/pubmed/19652721
http://dx.doi.org/10.1371/journal.pone.0006514
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author Pan, Weihong
Bodempudi, Vidya
Esfandyari, Tuba
Farassati, Faris
author_facet Pan, Weihong
Bodempudi, Vidya
Esfandyari, Tuba
Farassati, Faris
author_sort Pan, Weihong
collection PubMed
description Re-engineering the tropism of viruses is an attractive translational strategy for targeting cancer cells. The Ras signal transduction pathway is a central hub for a variety of pro-oncogenic events with a fundamental role in normal and neoplastic physiology. In this work we were interested in linking Ras activation to HSV-1 replication in a direct manner in order to generate a novel oncolytic herpes virus which can target cancer cells. To establish such link, we developed a mutant HSV-1 in which the expression of ICP4 (infected cell protein-4, a viral protein necessary for replication) is controlled by activation of ELK, a transcription factor down-stream of the Ras pathway and mainly activated by ERK (extracellular signal-regulated kinase, an important Ras effector pathway). This mutant HSV-1 was named as Signal-Smart 1 (SS1). A series of prostate cells were infected with the SS1 virus. Cells with elevated levels of ELK activation were preferentially infected by the SS1 virus, as demonstrated by increased levels of viral progeny, herpetic glycoprotein C and overall SS1 viral protein production. Upon exposure to SS1, the proliferation, invasiveness and colony formation capabilities of prostate cancer cells with increased ELK activation were significantly decreased (p<0.05), while the rate of apoptosis/necrosis in these cells was increased. Additionally, high Ras signaling cells infected with SS1 showed a prominent arrest in the G1 phase of the cell cycle as compared to cells exposed to parental HSV-1. The results of this study reveal the potential for re-modeling the host-herpes interaction to specifically interfere with the life of cancer cells with increased Ras signaling. SS1 also serves as a “prototype” for development of a family of signal-smart viruses which can target cancer cells on the basis of their signaling portfolio.
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spelling pubmed-27158842009-08-04 Utilizing Ras Signaling Pathway to Direct Selective Replication of Herpes Simplex Virus-1 Pan, Weihong Bodempudi, Vidya Esfandyari, Tuba Farassati, Faris PLoS One Research Article Re-engineering the tropism of viruses is an attractive translational strategy for targeting cancer cells. The Ras signal transduction pathway is a central hub for a variety of pro-oncogenic events with a fundamental role in normal and neoplastic physiology. In this work we were interested in linking Ras activation to HSV-1 replication in a direct manner in order to generate a novel oncolytic herpes virus which can target cancer cells. To establish such link, we developed a mutant HSV-1 in which the expression of ICP4 (infected cell protein-4, a viral protein necessary for replication) is controlled by activation of ELK, a transcription factor down-stream of the Ras pathway and mainly activated by ERK (extracellular signal-regulated kinase, an important Ras effector pathway). This mutant HSV-1 was named as Signal-Smart 1 (SS1). A series of prostate cells were infected with the SS1 virus. Cells with elevated levels of ELK activation were preferentially infected by the SS1 virus, as demonstrated by increased levels of viral progeny, herpetic glycoprotein C and overall SS1 viral protein production. Upon exposure to SS1, the proliferation, invasiveness and colony formation capabilities of prostate cancer cells with increased ELK activation were significantly decreased (p<0.05), while the rate of apoptosis/necrosis in these cells was increased. Additionally, high Ras signaling cells infected with SS1 showed a prominent arrest in the G1 phase of the cell cycle as compared to cells exposed to parental HSV-1. The results of this study reveal the potential for re-modeling the host-herpes interaction to specifically interfere with the life of cancer cells with increased Ras signaling. SS1 also serves as a “prototype” for development of a family of signal-smart viruses which can target cancer cells on the basis of their signaling portfolio. Public Library of Science 2009-08-04 /pmc/articles/PMC2715884/ /pubmed/19652721 http://dx.doi.org/10.1371/journal.pone.0006514 Text en Pan et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Pan, Weihong
Bodempudi, Vidya
Esfandyari, Tuba
Farassati, Faris
Utilizing Ras Signaling Pathway to Direct Selective Replication of Herpes Simplex Virus-1
title Utilizing Ras Signaling Pathway to Direct Selective Replication of Herpes Simplex Virus-1
title_full Utilizing Ras Signaling Pathway to Direct Selective Replication of Herpes Simplex Virus-1
title_fullStr Utilizing Ras Signaling Pathway to Direct Selective Replication of Herpes Simplex Virus-1
title_full_unstemmed Utilizing Ras Signaling Pathway to Direct Selective Replication of Herpes Simplex Virus-1
title_short Utilizing Ras Signaling Pathway to Direct Selective Replication of Herpes Simplex Virus-1
title_sort utilizing ras signaling pathway to direct selective replication of herpes simplex virus-1
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715884/
https://www.ncbi.nlm.nih.gov/pubmed/19652721
http://dx.doi.org/10.1371/journal.pone.0006514
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