Targeting hodgkin and reed–sternberg cells with an inhibitor of heat-shock protein 90: Molecular pathways of response and potential mechanisms of resistance

Autores
Segges, Priscilla; Corrêa, Stephany; Du Rocher, Bárbara; Vera Lozada, Gabriela; Krsticevic, Flavia Jorgelina; Arce, Debora Pamela; Sternberg, Cinthya; Abdelhay, Eliana; Hassan, Rocio
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Classical Hodgkin lymphoma (cHL) cells overexpress heat-shock protein 90 (HSP90), an important intracellular signaling hub regulating cell survival, which is emerging as a promising therapeutic target. Here, we report the antitumor effect of celastrol, an anti-inflammatory compound and a recognized HSP90 inhibitor, in Hodgkin and Reed-Sternberg cell lines. Two disparate responses were recorded. In KM-H2 cells, celastrol inhibited cell proliferation, induced G0/G1 arrest, and triggered apoptosis through the activation of caspase-3/7. Conversely, L428 cells exhibited resistance to the compound. A proteomic screening identified a total of 262 differentially expressed proteins in sensitive KM-H2 cells and revealed that celastrol’s toxicity involved the suppression of the MAPK/ERK (extracellular signal regulated kinase/mitogen activated protein kinase) pathway. The apoptotic effects were preceded by a decrease in RAS (proto-oncogene protein Ras), p-ERK1/2 (phospho-extracellular signal-regulated Kinase-1/2), and c-Fos (proto-oncogene protein c-Fos) protein levels, as validated by immunoblot analysis. The L428 resistant cells exhibited a marked induction of HSP27 mRNA and protein after celastrol treatment. Our results provide the first evidence that celastrol has antitumor effects in cHL cells through the suppression of the MAPK/ERK pathway. Resistance to celastrol has rarely been described, and our results suggest that in cHL it may be mediated by the upregulation of HSP27. The antitumor properties of celastrol against cHL and whether the disparate responses observed in vitro have clinical correlates deserve further research.
Fil: Segges, Priscilla. Instituto Nacional de Câncer; Brasil
Fil: Corrêa, Stephany. Instituto Nacional de Câncer; Brasil
Fil: Du Rocher, Bárbara. Fundación Oswaldo Cruz; Brasil. Instituto Nacional de Câncer; Brasil
Fil: Vera Lozada, Gabriela. Instituto Nacional de Câncer; Brasil
Fil: Krsticevic, Flavia Jorgelina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Centro Internacional Franco Argentino de Ciencias de la Información y de Sistemas. Universidad Nacional de Rosario. Centro Internacional Franco Argentino de Ciencias de la Información y de Sistemas; Argentina
Fil: Arce, Debora Pamela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones en Ciencias Agrarias de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Agrarias. Instituto de Investigaciones en Ciencias Agrarias de Rosario; Argentina
Fil: Sternberg, Cinthya. Universidade Federal do Rio de Janeiro; Brasil
Fil: Abdelhay, Eliana. Instituto Nacional de Câncer; Brasil
Fil: Hassan, Rocio. Instituto Nacional de Câncer; Brasil
Materia
CELASTROL
HEAT-SHOCK PROTEIN 90 (HSP90) INHIBITION
HODGKIN LYMPHOMA
HSP27
LABEL-FREE PROTEOMICS
MAPK/ERK PATHWAY
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/91825
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/91825
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Targeting hodgkin and reed–sternberg cells with an inhibitor of heat-shock protein 90: Molecular pathways of response and potential mechanisms of resistanceSegges, PriscillaCorrêa, StephanyDu Rocher, BárbaraVera Lozada, GabrielaKrsticevic, Flavia JorgelinaArce, Debora PamelaSternberg, CinthyaAbdelhay, ElianaHassan, RocioCELASTROLHEAT-SHOCK PROTEIN 90 (HSP90) INHIBITIONHODGKIN LYMPHOMAHSP27LABEL-FREE PROTEOMICSMAPK/ERK PATHWAYhttps://purl.org/becyt/ford/3.4https://purl.org/becyt/ford/3Classical Hodgkin lymphoma (cHL) cells overexpress heat-shock protein 90 (HSP90), an important intracellular signaling hub regulating cell survival, which is emerging as a promising therapeutic target. Here, we report the antitumor effect of celastrol, an anti-inflammatory compound and a recognized HSP90 inhibitor, in Hodgkin and Reed-Sternberg cell lines. Two disparate responses were recorded. In KM-H2 cells, celastrol inhibited cell proliferation, induced G0/G1 arrest, and triggered apoptosis through the activation of caspase-3/7. Conversely, L428 cells exhibited resistance to the compound. A proteomic screening identified a total of 262 differentially expressed proteins in sensitive KM-H2 cells and revealed that celastrol’s toxicity involved the suppression of the MAPK/ERK (extracellular signal regulated kinase/mitogen activated protein kinase) pathway. The apoptotic effects were preceded by a decrease in RAS (proto-oncogene protein Ras), p-ERK1/2 (phospho-extracellular signal-regulated Kinase-1/2), and c-Fos (proto-oncogene protein c-Fos) protein levels, as validated by immunoblot analysis. The L428 resistant cells exhibited a marked induction of HSP27 mRNA and protein after celastrol treatment. Our results provide the first evidence that celastrol has antitumor effects in cHL cells through the suppression of the MAPK/ERK pathway. Resistance to celastrol has rarely been described, and our results suggest that in cHL it may be mediated by the upregulation of HSP27. The antitumor properties of celastrol against cHL and whether the disparate responses observed in vitro have clinical correlates deserve further research.Fil: Segges, Priscilla. Instituto Nacional de Câncer; BrasilFil: Corrêa, Stephany. Instituto Nacional de Câncer; BrasilFil: Du Rocher, Bárbara. Fundación Oswaldo Cruz; Brasil. Instituto Nacional de Câncer; BrasilFil: Vera Lozada, Gabriela. Instituto Nacional de Câncer; BrasilFil: Krsticevic, Flavia Jorgelina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Centro Internacional Franco Argentino de Ciencias de la Información y de Sistemas. Universidad Nacional de Rosario. Centro Internacional Franco Argentino de Ciencias de la Información y de Sistemas; ArgentinaFil: Arce, Debora Pamela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones en Ciencias Agrarias de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Agrarias. Instituto de Investigaciones en Ciencias Agrarias de Rosario; ArgentinaFil: Sternberg, Cinthya. Universidade Federal do Rio de Janeiro; BrasilFil: Abdelhay, Eliana. Instituto Nacional de Câncer; BrasilFil: Hassan, Rocio. Instituto Nacional de Câncer; BrasilMolecular Diversity Preservation International2018-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/91825Segges, Priscilla; Corrêa, Stephany; Du Rocher, Bárbara; Vera Lozada, Gabriela; Krsticevic, Flavia Jorgelina; et al.; Targeting hodgkin and reed–sternberg cells with an inhibitor of heat-shock protein 90: Molecular pathways of response and potential mechanisms of resistance; Molecular Diversity Preservation International; International Journal of Molecular Sciences; 19; 3; 3-2018; 1-141422-0067CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.mdpi.com/1422-0067/19/3/836info:eu-repo/semantics/altIdentifier/doi/10.3390/ijms19030836info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:33:30Zoai:ri.conicet.gov.ar:11336/91825instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:33:31.029CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Targeting hodgkin and reed–sternberg cells with an inhibitor of heat-shock protein 90: Molecular pathways of response and potential mechanisms of resistance
title Targeting hodgkin and reed–sternberg cells with an inhibitor of heat-shock protein 90: Molecular pathways of response and potential mechanisms of resistance
spellingShingle Targeting hodgkin and reed–sternberg cells with an inhibitor of heat-shock protein 90: Molecular pathways of response and potential mechanisms of resistance
Segges, Priscilla
CELASTROL
HEAT-SHOCK PROTEIN 90 (HSP90) INHIBITION
HODGKIN LYMPHOMA
HSP27
LABEL-FREE PROTEOMICS
MAPK/ERK PATHWAY
title_short Targeting hodgkin and reed–sternberg cells with an inhibitor of heat-shock protein 90: Molecular pathways of response and potential mechanisms of resistance
title_full Targeting hodgkin and reed–sternberg cells with an inhibitor of heat-shock protein 90: Molecular pathways of response and potential mechanisms of resistance
title_fullStr Targeting hodgkin and reed–sternberg cells with an inhibitor of heat-shock protein 90: Molecular pathways of response and potential mechanisms of resistance
title_full_unstemmed Targeting hodgkin and reed–sternberg cells with an inhibitor of heat-shock protein 90: Molecular pathways of response and potential mechanisms of resistance
title_sort Targeting hodgkin and reed–sternberg cells with an inhibitor of heat-shock protein 90: Molecular pathways of response and potential mechanisms of resistance
dc.creator.none.fl_str_mv Segges, Priscilla
Corrêa, Stephany
Du Rocher, Bárbara
Vera Lozada, Gabriela
Krsticevic, Flavia Jorgelina
Arce, Debora Pamela
Sternberg, Cinthya
Abdelhay, Eliana
Hassan, Rocio
author Segges, Priscilla
author_facet Segges, Priscilla
Corrêa, Stephany
Du Rocher, Bárbara
Vera Lozada, Gabriela
Krsticevic, Flavia Jorgelina
Arce, Debora Pamela
Sternberg, Cinthya
Abdelhay, Eliana
Hassan, Rocio
author_role author
author2 Corrêa, Stephany
Du Rocher, Bárbara
Vera Lozada, Gabriela
Krsticevic, Flavia Jorgelina
Arce, Debora Pamela
Sternberg, Cinthya
Abdelhay, Eliana
Hassan, Rocio
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CELASTROL
HEAT-SHOCK PROTEIN 90 (HSP90) INHIBITION
HODGKIN LYMPHOMA
HSP27
LABEL-FREE PROTEOMICS
MAPK/ERK PATHWAY
topic CELASTROL
HEAT-SHOCK PROTEIN 90 (HSP90) INHIBITION
HODGKIN LYMPHOMA
HSP27
LABEL-FREE PROTEOMICS
MAPK/ERK PATHWAY
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.4
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Classical Hodgkin lymphoma (cHL) cells overexpress heat-shock protein 90 (HSP90), an important intracellular signaling hub regulating cell survival, which is emerging as a promising therapeutic target. Here, we report the antitumor effect of celastrol, an anti-inflammatory compound and a recognized HSP90 inhibitor, in Hodgkin and Reed-Sternberg cell lines. Two disparate responses were recorded. In KM-H2 cells, celastrol inhibited cell proliferation, induced G0/G1 arrest, and triggered apoptosis through the activation of caspase-3/7. Conversely, L428 cells exhibited resistance to the compound. A proteomic screening identified a total of 262 differentially expressed proteins in sensitive KM-H2 cells and revealed that celastrol’s toxicity involved the suppression of the MAPK/ERK (extracellular signal regulated kinase/mitogen activated protein kinase) pathway. The apoptotic effects were preceded by a decrease in RAS (proto-oncogene protein Ras), p-ERK1/2 (phospho-extracellular signal-regulated Kinase-1/2), and c-Fos (proto-oncogene protein c-Fos) protein levels, as validated by immunoblot analysis. The L428 resistant cells exhibited a marked induction of HSP27 mRNA and protein after celastrol treatment. Our results provide the first evidence that celastrol has antitumor effects in cHL cells through the suppression of the MAPK/ERK pathway. Resistance to celastrol has rarely been described, and our results suggest that in cHL it may be mediated by the upregulation of HSP27. The antitumor properties of celastrol against cHL and whether the disparate responses observed in vitro have clinical correlates deserve further research.
Fil: Segges, Priscilla. Instituto Nacional de Câncer; Brasil
Fil: Corrêa, Stephany. Instituto Nacional de Câncer; Brasil
Fil: Du Rocher, Bárbara. Fundación Oswaldo Cruz; Brasil. Instituto Nacional de Câncer; Brasil
Fil: Vera Lozada, Gabriela. Instituto Nacional de Câncer; Brasil
Fil: Krsticevic, Flavia Jorgelina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Centro Internacional Franco Argentino de Ciencias de la Información y de Sistemas. Universidad Nacional de Rosario. Centro Internacional Franco Argentino de Ciencias de la Información y de Sistemas; Argentina
Fil: Arce, Debora Pamela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones en Ciencias Agrarias de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Agrarias. Instituto de Investigaciones en Ciencias Agrarias de Rosario; Argentina
Fil: Sternberg, Cinthya. Universidade Federal do Rio de Janeiro; Brasil
Fil: Abdelhay, Eliana. Instituto Nacional de Câncer; Brasil
Fil: Hassan, Rocio. Instituto Nacional de Câncer; Brasil
description Classical Hodgkin lymphoma (cHL) cells overexpress heat-shock protein 90 (HSP90), an important intracellular signaling hub regulating cell survival, which is emerging as a promising therapeutic target. Here, we report the antitumor effect of celastrol, an anti-inflammatory compound and a recognized HSP90 inhibitor, in Hodgkin and Reed-Sternberg cell lines. Two disparate responses were recorded. In KM-H2 cells, celastrol inhibited cell proliferation, induced G0/G1 arrest, and triggered apoptosis through the activation of caspase-3/7. Conversely, L428 cells exhibited resistance to the compound. A proteomic screening identified a total of 262 differentially expressed proteins in sensitive KM-H2 cells and revealed that celastrol’s toxicity involved the suppression of the MAPK/ERK (extracellular signal regulated kinase/mitogen activated protein kinase) pathway. The apoptotic effects were preceded by a decrease in RAS (proto-oncogene protein Ras), p-ERK1/2 (phospho-extracellular signal-regulated Kinase-1/2), and c-Fos (proto-oncogene protein c-Fos) protein levels, as validated by immunoblot analysis. The L428 resistant cells exhibited a marked induction of HSP27 mRNA and protein after celastrol treatment. Our results provide the first evidence that celastrol has antitumor effects in cHL cells through the suppression of the MAPK/ERK pathway. Resistance to celastrol has rarely been described, and our results suggest that in cHL it may be mediated by the upregulation of HSP27. The antitumor properties of celastrol against cHL and whether the disparate responses observed in vitro have clinical correlates deserve further research.
publishDate 2018
dc.date.none.fl_str_mv 2018-03
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/91825
Segges, Priscilla; Corrêa, Stephany; Du Rocher, Bárbara; Vera Lozada, Gabriela; Krsticevic, Flavia Jorgelina; et al.; Targeting hodgkin and reed–sternberg cells with an inhibitor of heat-shock protein 90: Molecular pathways of response and potential mechanisms of resistance; Molecular Diversity Preservation International; International Journal of Molecular Sciences; 19; 3; 3-2018; 1-14
1422-0067
CONICET Digital
CONICET
url http://hdl.handle.net/11336/91825
identifier_str_mv Segges, Priscilla; Corrêa, Stephany; Du Rocher, Bárbara; Vera Lozada, Gabriela; Krsticevic, Flavia Jorgelina; et al.; Targeting hodgkin and reed–sternberg cells with an inhibitor of heat-shock protein 90: Molecular pathways of response and potential mechanisms of resistance; Molecular Diversity Preservation International; International Journal of Molecular Sciences; 19; 3; 3-2018; 1-14
1422-0067
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.mdpi.com/1422-0067/19/3/836
info:eu-repo/semantics/altIdentifier/doi/10.3390/ijms19030836
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Molecular Diversity Preservation International
publisher.none.fl_str_mv Molecular Diversity Preservation International
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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