KSHV G-protein coupled receptor vGPCR oncogenic signaling upregulation of Cyclooxygenase-2 expression mediates angiogenesis and tumorigenesis in Kaposi's sarcoma

Author summary Kaposi sarcoma (KS) is the most frequent AIDS-related cancer (AIDS-KS). The tumours originate in cells infected with a cancer-causing virus (KSHV). A gene encoded by the virus expresses a protein with oncogenic potential in the infected cells (vGPCR), which has the ability to promote...

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Autores: Medina, MV, D'Agostino, A, Ma, Q, Eroles, P, Cavallin, L, Chiozzini, C, Sapochnik, D, Cymeryng, C, Hyjek, E, Cesarman, E, Naipauer, J, Mesri, EA, Coso, OA
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:INCLIVA
Repositorio:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
OAI Identifier:oai:incliva.fundanetsuite.com:p15672
Acceso en línea:https://incliva.portalinvestigacion.com/publicaciones/15672
Access Level:acceso abierto
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spelling KSHV G-protein coupled receptor vGPCR oncogenic signaling upregulation of Cyclooxygenase-2 expression mediates angiogenesis and tumorigenesis in Kaposi's sarcomaMedina, MVD'Agostino, AMa, QEroles, PCavallin, LChiozzini, CSapochnik, DCymeryng, CHyjek, ECesarman, ENaipauer, JMesri, EACoso, OAAuthor summary Kaposi sarcoma (KS) is the most frequent AIDS-related cancer (AIDS-KS). The tumours originate in cells infected with a cancer-causing virus (KSHV). A gene encoded by the virus expresses a protein with oncogenic potential in the infected cells (vGPCR), which has the ability to promote cell transformation and angiogenesis driving KS tumorigenesis. Therefore, the identification of oncogenic intracellular signalling mechanisms triggered by vGPCR could be of therapeutic interest. Cyclooxygenase-2 (COX-2) is an inflammatory molecule involved in tumor angiogenesis that can be targeted by several FDA-approved non-steroidal anti-inflammatory drugs and specific inhibitors. Here, we demonstrate that vGPCR upregulates COX-2 activity and expression through upregulation of transcription and mRNA stability via an ERK1/2 dependent pathway. We also show that COX-2 activity is critical for vGPCR angiogenesis and oncogenesis using KSHV infection and mouse models. Consistent with a role in KS pathogenesis, we found that vGPCR upregulates COX-2 activity in endothelial cells, that it is essential for VEGF upregulation via vGPCR, and that it is expressed in KSHV infected cells of AIDS-KS lesions. These facts point to COX-2 as one of the molecular components of the vGPCR angiogenic switch in Kaposi Sarcoma and a potential target for chemoprevention and therapy. Kaposi's sarcoma-associated herpesvirus (KSHV) vGPCR is a constitutively active G protein-coupled receptor that subverts proliferative and inflammatory signaling pathways to induce cell transformation in Kaposi's sarcoma. Cyclooxygenase-2 (COX-2) is an inflammatory mediator that plays a key regulatory role in the activation of tumor angiogenesis. Hereby we demonstrate, using two different transformed mouse models, and tumorigenic full KSHV genome-bearing cells, including KSHV-Bac16 based mutant system with a vGPCR deletion, that vGPCR upregulates COX-2 expression and activity, signaling through selective MAPK cascades. We show that vGPCR expression triggers signaling pathways that upregulate COX-2 levels due to a dual effect upon both its gene promoter region and, in mature mRNA, the 3'UTR region that control mRNA stability. Both events are mediated by signaling through ERK1/2 MAPK pathway. Inhibition of COX-2 in vGPCR-transformed cells impairs vGPCR-driven angiogenesis and treatment with the COX-2-selective inhibitory drug Celecoxib produces a significant decrease in tumor growth, pointing to COX-2 activity as critical for vGPCR oncogenicityin vivoand indicating that COX-2-mediated angiogenesis could play a role in KS tumorigenesis. These results, along with the overexpression of COX-2 in KS lesions, define COX-2 as a potential target for the prevention and treatment of KSHV-oncogenesis.PUBLIC LIBRARY SCIENCE2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://incliva.portalinvestigacion.com/publicaciones/15672PLoS PathogensISSN: 15537366ISSNe: 15537374reponame:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVAinstname:INCLIVAInglésinfo:eu-repo/semantics/openAccessoai:incliva.fundanetsuite.com:p156722026-06-07T16:35:31Z
dc.title.none.fl_str_mv KSHV G-protein coupled receptor vGPCR oncogenic signaling upregulation of Cyclooxygenase-2 expression mediates angiogenesis and tumorigenesis in Kaposi's sarcoma
title KSHV G-protein coupled receptor vGPCR oncogenic signaling upregulation of Cyclooxygenase-2 expression mediates angiogenesis and tumorigenesis in Kaposi's sarcoma
spellingShingle KSHV G-protein coupled receptor vGPCR oncogenic signaling upregulation of Cyclooxygenase-2 expression mediates angiogenesis and tumorigenesis in Kaposi's sarcoma
Medina, MV
title_short KSHV G-protein coupled receptor vGPCR oncogenic signaling upregulation of Cyclooxygenase-2 expression mediates angiogenesis and tumorigenesis in Kaposi's sarcoma
title_full KSHV G-protein coupled receptor vGPCR oncogenic signaling upregulation of Cyclooxygenase-2 expression mediates angiogenesis and tumorigenesis in Kaposi's sarcoma
title_fullStr KSHV G-protein coupled receptor vGPCR oncogenic signaling upregulation of Cyclooxygenase-2 expression mediates angiogenesis and tumorigenesis in Kaposi's sarcoma
title_full_unstemmed KSHV G-protein coupled receptor vGPCR oncogenic signaling upregulation of Cyclooxygenase-2 expression mediates angiogenesis and tumorigenesis in Kaposi's sarcoma
title_sort KSHV G-protein coupled receptor vGPCR oncogenic signaling upregulation of Cyclooxygenase-2 expression mediates angiogenesis and tumorigenesis in Kaposi's sarcoma
dc.creator.none.fl_str_mv Medina, MV
D'Agostino, A
Ma, Q
Eroles, P
Cavallin, L
Chiozzini, C
Sapochnik, D
Cymeryng, C
Hyjek, E
Cesarman, E
Naipauer, J
Mesri, EA
Coso, OA
author Medina, MV
author_facet Medina, MV
D'Agostino, A
Ma, Q
Eroles, P
Cavallin, L
Chiozzini, C
Sapochnik, D
Cymeryng, C
Hyjek, E
Cesarman, E
Naipauer, J
Mesri, EA
Coso, OA
author_role author
author2 D'Agostino, A
Ma, Q
Eroles, P
Cavallin, L
Chiozzini, C
Sapochnik, D
Cymeryng, C
Hyjek, E
Cesarman, E
Naipauer, J
Mesri, EA
Coso, OA
author2_role author
author
author
author
author
author
author
author
author
author
author
author
description Author summary Kaposi sarcoma (KS) is the most frequent AIDS-related cancer (AIDS-KS). The tumours originate in cells infected with a cancer-causing virus (KSHV). A gene encoded by the virus expresses a protein with oncogenic potential in the infected cells (vGPCR), which has the ability to promote cell transformation and angiogenesis driving KS tumorigenesis. Therefore, the identification of oncogenic intracellular signalling mechanisms triggered by vGPCR could be of therapeutic interest. Cyclooxygenase-2 (COX-2) is an inflammatory molecule involved in tumor angiogenesis that can be targeted by several FDA-approved non-steroidal anti-inflammatory drugs and specific inhibitors. Here, we demonstrate that vGPCR upregulates COX-2 activity and expression through upregulation of transcription and mRNA stability via an ERK1/2 dependent pathway. We also show that COX-2 activity is critical for vGPCR angiogenesis and oncogenesis using KSHV infection and mouse models. Consistent with a role in KS pathogenesis, we found that vGPCR upregulates COX-2 activity in endothelial cells, that it is essential for VEGF upregulation via vGPCR, and that it is expressed in KSHV infected cells of AIDS-KS lesions. These facts point to COX-2 as one of the molecular components of the vGPCR angiogenic switch in Kaposi Sarcoma and a potential target for chemoprevention and therapy. Kaposi's sarcoma-associated herpesvirus (KSHV) vGPCR is a constitutively active G protein-coupled receptor that subverts proliferative and inflammatory signaling pathways to induce cell transformation in Kaposi's sarcoma. Cyclooxygenase-2 (COX-2) is an inflammatory mediator that plays a key regulatory role in the activation of tumor angiogenesis. Hereby we demonstrate, using two different transformed mouse models, and tumorigenic full KSHV genome-bearing cells, including KSHV-Bac16 based mutant system with a vGPCR deletion, that vGPCR upregulates COX-2 expression and activity, signaling through selective MAPK cascades. We show that vGPCR expression triggers signaling pathways that upregulate COX-2 levels due to a dual effect upon both its gene promoter region and, in mature mRNA, the 3'UTR region that control mRNA stability. Both events are mediated by signaling through ERK1/2 MAPK pathway. Inhibition of COX-2 in vGPCR-transformed cells impairs vGPCR-driven angiogenesis and treatment with the COX-2-selective inhibitory drug Celecoxib produces a significant decrease in tumor growth, pointing to COX-2 activity as critical for vGPCR oncogenicityin vivoand indicating that COX-2-mediated angiogenesis could play a role in KS tumorigenesis. These results, along with the overexpression of COX-2 in KS lesions, define COX-2 as a potential target for the prevention and treatment of KSHV-oncogenesis.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://incliva.portalinvestigacion.com/publicaciones/15672
url https://incliva.portalinvestigacion.com/publicaciones/15672
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv PUBLIC LIBRARY SCIENCE
publisher.none.fl_str_mv PUBLIC LIBRARY SCIENCE
dc.source.none.fl_str_mv PLoS Pathogens
ISSN: 15537366
ISSNe: 15537374
reponame:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
instname:INCLIVA
instname_str INCLIVA
reponame_str r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
collection r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
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