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KSHV-induced ligand mediated activation of PDGF receptor-alpha drives Kaposi's sarcomagenesis
Kaposi’s sarcoma (KS) herpesvirus (KSHV) causes KS, an angiogenic AIDS-associated spindle-cell neoplasm, by activating host oncogenic signaling cascades through autocrine and paracrine mechanisms. Tyrosine kinase receptor (RTK) proteomic arrays, identified PDGF receptor-alpha (PDGFRA) as the predomi...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053240/ https://www.ncbi.nlm.nih.gov/pubmed/29985958 http://dx.doi.org/10.1371/journal.ppat.1007175 |
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author | Cavallin, Lucas E. Ma, Qi Naipauer, Julian Gupta, Sachin Kurian, Mani Locatelli, Paola Romanelli, Paolo Nadji, Mehrdad Goldschmidt-Clermont, Pascal J. Mesri, Enrique A. |
author_facet | Cavallin, Lucas E. Ma, Qi Naipauer, Julian Gupta, Sachin Kurian, Mani Locatelli, Paola Romanelli, Paolo Nadji, Mehrdad Goldschmidt-Clermont, Pascal J. Mesri, Enrique A. |
author_sort | Cavallin, Lucas E. |
collection | PubMed |
description | Kaposi’s sarcoma (KS) herpesvirus (KSHV) causes KS, an angiogenic AIDS-associated spindle-cell neoplasm, by activating host oncogenic signaling cascades through autocrine and paracrine mechanisms. Tyrosine kinase receptor (RTK) proteomic arrays, identified PDGF receptor-alpha (PDGFRA) as the predominantly-activated RTK in KSHV-induced mouse KS-tumors. We show that: 1) KSHV lytic replication and the vGPCR can activate PDGFRA through upregulation of its ligands PDGFA/B, which increase c-myc, VEGF and KSHV gene expression in infected cells 2) KSHV infected spindle cells of most AIDS-KS lesions display robust phospho-PDGFRA staining 3) blocking PDGFRA-signaling with N-acetyl-cysteine, RTK-inhibitors Imatinib and Sunitinib, or dominant-negative PDGFRA inhibits tumorigenesis 4) PDGFRA D842V activating-mutation confers resistance to Imatinib in mouse-KS tumorigenesis. Our data show that KSHV usurps sarcomagenic PDGFRA signaling to drive KS. This and the fact that PDGFRA drives non-viral sarcomas highlights the importance for KSHV-induced ligand-mediated activation of PDGFRA in KS sarcomagenesis and shows that this oncogenic axis could be successfully blocked to impede KS tumor growth. |
format | Online Article Text |
id | pubmed-6053240 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-60532402018-07-27 KSHV-induced ligand mediated activation of PDGF receptor-alpha drives Kaposi's sarcomagenesis Cavallin, Lucas E. Ma, Qi Naipauer, Julian Gupta, Sachin Kurian, Mani Locatelli, Paola Romanelli, Paolo Nadji, Mehrdad Goldschmidt-Clermont, Pascal J. Mesri, Enrique A. PLoS Pathog Research Article Kaposi’s sarcoma (KS) herpesvirus (KSHV) causes KS, an angiogenic AIDS-associated spindle-cell neoplasm, by activating host oncogenic signaling cascades through autocrine and paracrine mechanisms. Tyrosine kinase receptor (RTK) proteomic arrays, identified PDGF receptor-alpha (PDGFRA) as the predominantly-activated RTK in KSHV-induced mouse KS-tumors. We show that: 1) KSHV lytic replication and the vGPCR can activate PDGFRA through upregulation of its ligands PDGFA/B, which increase c-myc, VEGF and KSHV gene expression in infected cells 2) KSHV infected spindle cells of most AIDS-KS lesions display robust phospho-PDGFRA staining 3) blocking PDGFRA-signaling with N-acetyl-cysteine, RTK-inhibitors Imatinib and Sunitinib, or dominant-negative PDGFRA inhibits tumorigenesis 4) PDGFRA D842V activating-mutation confers resistance to Imatinib in mouse-KS tumorigenesis. Our data show that KSHV usurps sarcomagenic PDGFRA signaling to drive KS. This and the fact that PDGFRA drives non-viral sarcomas highlights the importance for KSHV-induced ligand-mediated activation of PDGFRA in KS sarcomagenesis and shows that this oncogenic axis could be successfully blocked to impede KS tumor growth. Public Library of Science 2018-07-09 /pmc/articles/PMC6053240/ /pubmed/29985958 http://dx.doi.org/10.1371/journal.ppat.1007175 Text en © 2018 Cavallin 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 (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Cavallin, Lucas E. Ma, Qi Naipauer, Julian Gupta, Sachin Kurian, Mani Locatelli, Paola Romanelli, Paolo Nadji, Mehrdad Goldschmidt-Clermont, Pascal J. Mesri, Enrique A. KSHV-induced ligand mediated activation of PDGF receptor-alpha drives Kaposi's sarcomagenesis |
title | KSHV-induced ligand mediated activation of PDGF receptor-alpha drives Kaposi's sarcomagenesis |
title_full | KSHV-induced ligand mediated activation of PDGF receptor-alpha drives Kaposi's sarcomagenesis |
title_fullStr | KSHV-induced ligand mediated activation of PDGF receptor-alpha drives Kaposi's sarcomagenesis |
title_full_unstemmed | KSHV-induced ligand mediated activation of PDGF receptor-alpha drives Kaposi's sarcomagenesis |
title_short | KSHV-induced ligand mediated activation of PDGF receptor-alpha drives Kaposi's sarcomagenesis |
title_sort | kshv-induced ligand mediated activation of pdgf receptor-alpha drives kaposi's sarcomagenesis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053240/ https://www.ncbi.nlm.nih.gov/pubmed/29985958 http://dx.doi.org/10.1371/journal.ppat.1007175 |
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