Transcriptional activation of HIF-1 by a ROSERK axis underlies the resistance to photodynamic therapy
- Autores
- Lamberti, María Julia; Pansa, Maria Florencia; Vera, Renzo Emanuel; Fernandez Zapico, Martin Ernesto; Rumie Vittar, Natalia Belen; Rivarola, Viviana
- Año de publicación
- 2017
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Photodynamic therapy (PDT), a promising treatment option for cancer, involves the activation of a photosensitizer (PS) by local irradiation with visible light. Excitation of the PS leads to a series of photochemical reactions and consequently the local generation of harmful reactive oxygen species (ROS) causing limited or none systemic defects. However, the development of resistance to this promising therapy has slowed down its translation into the clinical practice. Thus, there is an increase need in understanding of the molecular mechanism underlying resistance to PDT. Here, we aimed to examine whether a relationship exists between PDT outcome and ROS-involvement in the resistance mechanism in photosensitized cancer cells. In order to recapitulate tumor architecture of the respective original tumor, we developed a multicellular three-dimensional spheroid system comprising a normoxic periphery, surrounding a hypoxic core. Using Me-ALA, a prodrug of the PS PpIX, in human colorectal spheroids we demonstrate that HIF-1 transcriptional activity was strongly up-regulated and mediates PDT resistant phenotype. RNAi knockdown of HIF-1 impairs resistance to PDT. Oxidative stress-mediated activation of ERK1/2 followed PDT was involved on positive modulation of HIF-1 transcriptional activity after photodynamic treatment. ROS scavenging and MEK/ERK pathway inhibition abrogated the PDT-mediated HIF-1 upregulation. Together our data demonstrate that resistance to PDT is in part mediated by the activation of a ROS-ERK1/2-HIF-1 axis, thus, identifying novel therapeutic targets that could be used in combination with PDT.
Fil: Lamberti, María Julia. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina
Fil: Pansa, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; Argentina
Fil: Vera, Renzo Emanuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; Argentina
Fil: Fernandez Zapico, Martin Ernesto. Schulze Center for Novel Therapeutics; Estados Unidos
Fil: Rumie Vittar, Natalia Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas, Fisicoquímicas y Naturales. Departamento de Biología Molecular. Sección Química Biológica; Argentina
Fil: Rivarola, Viviana. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina - Materia
-
CANCER
TERAPIA FOTODINAMICA
MICROAMBIENTE TUMORAL - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/80561
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Transcriptional activation of HIF-1 by a ROSERK axis underlies the resistance to photodynamic therapyLamberti, María JuliaPansa, Maria FlorenciaVera, Renzo EmanuelFernandez Zapico, Martin ErnestoRumie Vittar, Natalia BelenRivarola, VivianaCANCERTERAPIA FOTODINAMICAMICROAMBIENTE TUMORALhttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Photodynamic therapy (PDT), a promising treatment option for cancer, involves the activation of a photosensitizer (PS) by local irradiation with visible light. Excitation of the PS leads to a series of photochemical reactions and consequently the local generation of harmful reactive oxygen species (ROS) causing limited or none systemic defects. However, the development of resistance to this promising therapy has slowed down its translation into the clinical practice. Thus, there is an increase need in understanding of the molecular mechanism underlying resistance to PDT. Here, we aimed to examine whether a relationship exists between PDT outcome and ROS-involvement in the resistance mechanism in photosensitized cancer cells. In order to recapitulate tumor architecture of the respective original tumor, we developed a multicellular three-dimensional spheroid system comprising a normoxic periphery, surrounding a hypoxic core. Using Me-ALA, a prodrug of the PS PpIX, in human colorectal spheroids we demonstrate that HIF-1 transcriptional activity was strongly up-regulated and mediates PDT resistant phenotype. RNAi knockdown of HIF-1 impairs resistance to PDT. Oxidative stress-mediated activation of ERK1/2 followed PDT was involved on positive modulation of HIF-1 transcriptional activity after photodynamic treatment. ROS scavenging and MEK/ERK pathway inhibition abrogated the PDT-mediated HIF-1 upregulation. Together our data demonstrate that resistance to PDT is in part mediated by the activation of a ROS-ERK1/2-HIF-1 axis, thus, identifying novel therapeutic targets that could be used in combination with PDT.Fil: Lamberti, María Julia. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Pansa, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; ArgentinaFil: Vera, Renzo Emanuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; ArgentinaFil: Fernandez Zapico, Martin Ernesto. Schulze Center for Novel Therapeutics; Estados UnidosFil: Rumie Vittar, Natalia Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas, Fisicoquímicas y Naturales. Departamento de Biología Molecular. Sección Química Biológica; ArgentinaFil: Rivarola, Viviana. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaPublic Library of Science2017-05-17info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/80561Lamberti, María Julia; Pansa, Maria Florencia; Vera, Renzo Emanuel; Fernandez Zapico, Martin Ernesto; Rumie Vittar, Natalia Belen; et al.; Transcriptional activation of HIF-1 by a ROSERK axis underlies the resistance to photodynamic therapy; Public Library of Science; Plos One; 12; 5; 17-5-20171932-6203CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0177801info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pone.0177801info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:05:27Zoai:ri.conicet.gov.ar:11336/80561instacron: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:34982025-09-03 10:05:28.243CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Transcriptional activation of HIF-1 by a ROSERK axis underlies the resistance to photodynamic therapy |
title |
Transcriptional activation of HIF-1 by a ROSERK axis underlies the resistance to photodynamic therapy |
spellingShingle |
Transcriptional activation of HIF-1 by a ROSERK axis underlies the resistance to photodynamic therapy Lamberti, María Julia CANCER TERAPIA FOTODINAMICA MICROAMBIENTE TUMORAL |
title_short |
Transcriptional activation of HIF-1 by a ROSERK axis underlies the resistance to photodynamic therapy |
title_full |
Transcriptional activation of HIF-1 by a ROSERK axis underlies the resistance to photodynamic therapy |
title_fullStr |
Transcriptional activation of HIF-1 by a ROSERK axis underlies the resistance to photodynamic therapy |
title_full_unstemmed |
Transcriptional activation of HIF-1 by a ROSERK axis underlies the resistance to photodynamic therapy |
title_sort |
Transcriptional activation of HIF-1 by a ROSERK axis underlies the resistance to photodynamic therapy |
dc.creator.none.fl_str_mv |
Lamberti, María Julia Pansa, Maria Florencia Vera, Renzo Emanuel Fernandez Zapico, Martin Ernesto Rumie Vittar, Natalia Belen Rivarola, Viviana |
author |
Lamberti, María Julia |
author_facet |
Lamberti, María Julia Pansa, Maria Florencia Vera, Renzo Emanuel Fernandez Zapico, Martin Ernesto Rumie Vittar, Natalia Belen Rivarola, Viviana |
author_role |
author |
author2 |
Pansa, Maria Florencia Vera, Renzo Emanuel Fernandez Zapico, Martin Ernesto Rumie Vittar, Natalia Belen Rivarola, Viviana |
author2_role |
author author author author author |
dc.subject.none.fl_str_mv |
CANCER TERAPIA FOTODINAMICA MICROAMBIENTE TUMORAL |
topic |
CANCER TERAPIA FOTODINAMICA MICROAMBIENTE TUMORAL |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/3.3 https://purl.org/becyt/ford/3 |
dc.description.none.fl_txt_mv |
Photodynamic therapy (PDT), a promising treatment option for cancer, involves the activation of a photosensitizer (PS) by local irradiation with visible light. Excitation of the PS leads to a series of photochemical reactions and consequently the local generation of harmful reactive oxygen species (ROS) causing limited or none systemic defects. However, the development of resistance to this promising therapy has slowed down its translation into the clinical practice. Thus, there is an increase need in understanding of the molecular mechanism underlying resistance to PDT. Here, we aimed to examine whether a relationship exists between PDT outcome and ROS-involvement in the resistance mechanism in photosensitized cancer cells. In order to recapitulate tumor architecture of the respective original tumor, we developed a multicellular three-dimensional spheroid system comprising a normoxic periphery, surrounding a hypoxic core. Using Me-ALA, a prodrug of the PS PpIX, in human colorectal spheroids we demonstrate that HIF-1 transcriptional activity was strongly up-regulated and mediates PDT resistant phenotype. RNAi knockdown of HIF-1 impairs resistance to PDT. Oxidative stress-mediated activation of ERK1/2 followed PDT was involved on positive modulation of HIF-1 transcriptional activity after photodynamic treatment. ROS scavenging and MEK/ERK pathway inhibition abrogated the PDT-mediated HIF-1 upregulation. Together our data demonstrate that resistance to PDT is in part mediated by the activation of a ROS-ERK1/2-HIF-1 axis, thus, identifying novel therapeutic targets that could be used in combination with PDT. Fil: Lamberti, María Julia. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina Fil: Pansa, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; Argentina Fil: Vera, Renzo Emanuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; Argentina Fil: Fernandez Zapico, Martin Ernesto. Schulze Center for Novel Therapeutics; Estados Unidos Fil: Rumie Vittar, Natalia Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas, Fisicoquímicas y Naturales. Departamento de Biología Molecular. Sección Química Biológica; Argentina Fil: Rivarola, Viviana. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina |
description |
Photodynamic therapy (PDT), a promising treatment option for cancer, involves the activation of a photosensitizer (PS) by local irradiation with visible light. Excitation of the PS leads to a series of photochemical reactions and consequently the local generation of harmful reactive oxygen species (ROS) causing limited or none systemic defects. However, the development of resistance to this promising therapy has slowed down its translation into the clinical practice. Thus, there is an increase need in understanding of the molecular mechanism underlying resistance to PDT. Here, we aimed to examine whether a relationship exists between PDT outcome and ROS-involvement in the resistance mechanism in photosensitized cancer cells. In order to recapitulate tumor architecture of the respective original tumor, we developed a multicellular three-dimensional spheroid system comprising a normoxic periphery, surrounding a hypoxic core. Using Me-ALA, a prodrug of the PS PpIX, in human colorectal spheroids we demonstrate that HIF-1 transcriptional activity was strongly up-regulated and mediates PDT resistant phenotype. RNAi knockdown of HIF-1 impairs resistance to PDT. Oxidative stress-mediated activation of ERK1/2 followed PDT was involved on positive modulation of HIF-1 transcriptional activity after photodynamic treatment. ROS scavenging and MEK/ERK pathway inhibition abrogated the PDT-mediated HIF-1 upregulation. Together our data demonstrate that resistance to PDT is in part mediated by the activation of a ROS-ERK1/2-HIF-1 axis, thus, identifying novel therapeutic targets that could be used in combination with PDT. |
publishDate |
2017 |
dc.date.none.fl_str_mv |
2017-05-17 |
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/11336/80561 Lamberti, María Julia; Pansa, Maria Florencia; Vera, Renzo Emanuel; Fernandez Zapico, Martin Ernesto; Rumie Vittar, Natalia Belen; et al.; Transcriptional activation of HIF-1 by a ROSERK axis underlies the resistance to photodynamic therapy; Public Library of Science; Plos One; 12; 5; 17-5-2017 1932-6203 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/80561 |
identifier_str_mv |
Lamberti, María Julia; Pansa, Maria Florencia; Vera, Renzo Emanuel; Fernandez Zapico, Martin Ernesto; Rumie Vittar, Natalia Belen; et al.; Transcriptional activation of HIF-1 by a ROSERK axis underlies the resistance to photodynamic therapy; Public Library of Science; Plos One; 12; 5; 17-5-2017 1932-6203 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0177801 info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pone.0177801 |
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 |
Public Library of Science |
publisher.none.fl_str_mv |
Public Library of Science |
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reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
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Consejo Nacional de Investigaciones Científicas y Técnicas |
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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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