Novel role of VMP1 as modifier of the pancreatic tumor cell response to chemotherapeutic drugs

Autores
Gilabert, Mariana; Vaccaro, Maria Ines; Fernandez Zapico, Martín E.; Calvo, Ezequiel L.; Turrini, Olivier; Secq, Véronique; Garcia, Stéphanie; Moutardier, Vincent; Lomberk, Gwen; Dusetti, Nelson; Urrutia, Raul; Iovanna, Juan L.
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
We hypothesized that inhibiting molecules that mediate the adaptation response to cellular stress can antagonize the resistance of pancreatic cancer cells to chemotherapeutic drugs. Toward this end, here, we investigated how VMP1, a stress-induced autophagy-associated protein, modulate stress responses triggered by chemotherapeutic agents in PDAC. We find that VMP1 is particularly over-expressed in poorly differentiated human pancreatic cancer. Pharmacological studies show that drugs that work, in part, via the endoplasmic reticulum stress response, induce VMP1 expression. Similarly, VMP1 is induced by known endoplasmic reticulum stress activators. Genetic inactivation of VMP1 using RNAi-based antagonize the pancreatic cancer stress response to antitumoral agents. Functionally, we find that VMP1 regulates both autophagy and chemotherapeutic resistance even in the presence of chloroquin, ATG5 or Beclin 1 siRNAs, or a Beclin 1-binding VMP1 mutant. In addition, VMP1 modulates endoplasmic reticulum stress independently of its coupling to the molecular and cellular autophagy machinery. Preclinical studies demonstrate that xenografts expressing an inducible and tractable form of VMP1 show increased resistance to the gemcitabine treatment. These results underscore a novel role for VMP1 as a potential therapeutic target for combinatorial therapies aimed at sensitizing pancreatic cancer cells to chemotherapeutic agents as well as provide novel molecular mechanisms to better understand this phenomenon.
Fil: Gilabert, Mariana. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; Francia
Fil: Vaccaro, Maria Ines. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular; Argentina
Fil: Fernandez Zapico, Martín E.. Mayo Clinic Cancer Center; Estados Unidos
Fil: Calvo, Ezequiel L.. Molecular Endocrinology and Oncology Research Center; Canadá
Fil: Turrini, Olivier. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; Francia
Fil: Secq, Véronique. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; Francia
Fil: Garcia, Stéphanie. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; Francia
Fil: Moutardier, Vincent. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; Francia
Fil: Lomberk, Gwen. Mayo Clinic; Estados Unidos
Fil: Dusetti, Nelson. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; Francia
Fil: Urrutia, Raul. Mayo Clinic; Estados Unidos
Fil: Iovanna, Juan L.. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; Francia
Materia
VMP1
Pancreatic cancer
Autophagy
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/11462
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/11462
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Novel role of VMP1 as modifier of the pancreatic tumor cell response to chemotherapeutic drugsGilabert, MarianaVaccaro, Maria InesFernandez Zapico, Martín E.Calvo, Ezequiel L.Turrini, OlivierSecq, VéroniqueGarcia, Stéphanie Moutardier, VincentLomberk, GwenDusetti, NelsonUrrutia, RaulIovanna, Juan L.VMP1Pancreatic cancerAutophagyhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3We hypothesized that inhibiting molecules that mediate the adaptation response to cellular stress can antagonize the resistance of pancreatic cancer cells to chemotherapeutic drugs. Toward this end, here, we investigated how VMP1, a stress-induced autophagy-associated protein, modulate stress responses triggered by chemotherapeutic agents in PDAC. We find that VMP1 is particularly over-expressed in poorly differentiated human pancreatic cancer. Pharmacological studies show that drugs that work, in part, via the endoplasmic reticulum stress response, induce VMP1 expression. Similarly, VMP1 is induced by known endoplasmic reticulum stress activators. Genetic inactivation of VMP1 using RNAi-based antagonize the pancreatic cancer stress response to antitumoral agents. Functionally, we find that VMP1 regulates both autophagy and chemotherapeutic resistance even in the presence of chloroquin, ATG5 or Beclin 1 siRNAs, or a Beclin 1-binding VMP1 mutant. In addition, VMP1 modulates endoplasmic reticulum stress independently of its coupling to the molecular and cellular autophagy machinery. Preclinical studies demonstrate that xenografts expressing an inducible and tractable form of VMP1 show increased resistance to the gemcitabine treatment. These results underscore a novel role for VMP1 as a potential therapeutic target for combinatorial therapies aimed at sensitizing pancreatic cancer cells to chemotherapeutic agents as well as provide novel molecular mechanisms to better understand this phenomenon.Fil: Gilabert, Mariana. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; FranciaFil: Vaccaro, Maria Ines. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Fernandez Zapico, Martín E.. Mayo Clinic Cancer Center; Estados UnidosFil: Calvo, Ezequiel L.. Molecular Endocrinology and Oncology Research Center; CanadáFil: Turrini, Olivier. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; FranciaFil: Secq, Véronique. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; FranciaFil: Garcia, Stéphanie. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; FranciaFil: Moutardier, Vincent. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; FranciaFil: Lomberk, Gwen. Mayo Clinic; Estados UnidosFil: Dusetti, Nelson. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; FranciaFil: Urrutia, Raul. Mayo Clinic; Estados UnidosFil: Iovanna, Juan L.. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; FranciaWiley2013-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/11462Gilabert, Mariana; Vaccaro, Maria Ines; Fernandez Zapico, Martín E.; Calvo, Ezequiel L.; Turrini, Olivier; et al.; Novel role of VMP1 as modifier of the pancreatic tumor cell response to chemotherapeutic drugs; Wiley; Journal of Cell Physiology; 228; 9; 9-2013; 1834-18431097-4652enginfo:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048029/info:eu-repo/semantics/altIdentifier/doi/info:eu-repo/semantics/altIdentifier/doi/10.1002/jcp.24343info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:34:18Zoai:ri.conicet.gov.ar:11336/11462instacron: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 09:34:18.847CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Novel role of VMP1 as modifier of the pancreatic tumor cell response to chemotherapeutic drugs
title Novel role of VMP1 as modifier of the pancreatic tumor cell response to chemotherapeutic drugs
spellingShingle Novel role of VMP1 as modifier of the pancreatic tumor cell response to chemotherapeutic drugs
Gilabert, Mariana
VMP1
Pancreatic cancer
Autophagy
title_short Novel role of VMP1 as modifier of the pancreatic tumor cell response to chemotherapeutic drugs
title_full Novel role of VMP1 as modifier of the pancreatic tumor cell response to chemotherapeutic drugs
title_fullStr Novel role of VMP1 as modifier of the pancreatic tumor cell response to chemotherapeutic drugs
title_full_unstemmed Novel role of VMP1 as modifier of the pancreatic tumor cell response to chemotherapeutic drugs
title_sort Novel role of VMP1 as modifier of the pancreatic tumor cell response to chemotherapeutic drugs
dc.creator.none.fl_str_mv Gilabert, Mariana
Vaccaro, Maria Ines
Fernandez Zapico, Martín E.
Calvo, Ezequiel L.
Turrini, Olivier
Secq, Véronique
Garcia, Stéphanie
Moutardier, Vincent
Lomberk, Gwen
Dusetti, Nelson
Urrutia, Raul
Iovanna, Juan L.
author Gilabert, Mariana
author_facet Gilabert, Mariana
Vaccaro, Maria Ines
Fernandez Zapico, Martín E.
Calvo, Ezequiel L.
Turrini, Olivier
Secq, Véronique
Garcia, Stéphanie
Moutardier, Vincent
Lomberk, Gwen
Dusetti, Nelson
Urrutia, Raul
Iovanna, Juan L.
author_role author
author2 Vaccaro, Maria Ines
Fernandez Zapico, Martín E.
Calvo, Ezequiel L.
Turrini, Olivier
Secq, Véronique
Garcia, Stéphanie
Moutardier, Vincent
Lomberk, Gwen
Dusetti, Nelson
Urrutia, Raul
Iovanna, Juan L.
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv VMP1
Pancreatic cancer
Autophagy
topic VMP1
Pancreatic cancer
Autophagy
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv We hypothesized that inhibiting molecules that mediate the adaptation response to cellular stress can antagonize the resistance of pancreatic cancer cells to chemotherapeutic drugs. Toward this end, here, we investigated how VMP1, a stress-induced autophagy-associated protein, modulate stress responses triggered by chemotherapeutic agents in PDAC. We find that VMP1 is particularly over-expressed in poorly differentiated human pancreatic cancer. Pharmacological studies show that drugs that work, in part, via the endoplasmic reticulum stress response, induce VMP1 expression. Similarly, VMP1 is induced by known endoplasmic reticulum stress activators. Genetic inactivation of VMP1 using RNAi-based antagonize the pancreatic cancer stress response to antitumoral agents. Functionally, we find that VMP1 regulates both autophagy and chemotherapeutic resistance even in the presence of chloroquin, ATG5 or Beclin 1 siRNAs, or a Beclin 1-binding VMP1 mutant. In addition, VMP1 modulates endoplasmic reticulum stress independently of its coupling to the molecular and cellular autophagy machinery. Preclinical studies demonstrate that xenografts expressing an inducible and tractable form of VMP1 show increased resistance to the gemcitabine treatment. These results underscore a novel role for VMP1 as a potential therapeutic target for combinatorial therapies aimed at sensitizing pancreatic cancer cells to chemotherapeutic agents as well as provide novel molecular mechanisms to better understand this phenomenon.
Fil: Gilabert, Mariana. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; Francia
Fil: Vaccaro, Maria Ines. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular; Argentina
Fil: Fernandez Zapico, Martín E.. Mayo Clinic Cancer Center; Estados Unidos
Fil: Calvo, Ezequiel L.. Molecular Endocrinology and Oncology Research Center; Canadá
Fil: Turrini, Olivier. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; Francia
Fil: Secq, Véronique. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; Francia
Fil: Garcia, Stéphanie. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; Francia
Fil: Moutardier, Vincent. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; Francia
Fil: Lomberk, Gwen. Mayo Clinic; Estados Unidos
Fil: Dusetti, Nelson. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; Francia
Fil: Urrutia, Raul. Mayo Clinic; Estados Unidos
Fil: Iovanna, Juan L.. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; Francia
description We hypothesized that inhibiting molecules that mediate the adaptation response to cellular stress can antagonize the resistance of pancreatic cancer cells to chemotherapeutic drugs. Toward this end, here, we investigated how VMP1, a stress-induced autophagy-associated protein, modulate stress responses triggered by chemotherapeutic agents in PDAC. We find that VMP1 is particularly over-expressed in poorly differentiated human pancreatic cancer. Pharmacological studies show that drugs that work, in part, via the endoplasmic reticulum stress response, induce VMP1 expression. Similarly, VMP1 is induced by known endoplasmic reticulum stress activators. Genetic inactivation of VMP1 using RNAi-based antagonize the pancreatic cancer stress response to antitumoral agents. Functionally, we find that VMP1 regulates both autophagy and chemotherapeutic resistance even in the presence of chloroquin, ATG5 or Beclin 1 siRNAs, or a Beclin 1-binding VMP1 mutant. In addition, VMP1 modulates endoplasmic reticulum stress independently of its coupling to the molecular and cellular autophagy machinery. Preclinical studies demonstrate that xenografts expressing an inducible and tractable form of VMP1 show increased resistance to the gemcitabine treatment. These results underscore a novel role for VMP1 as a potential therapeutic target for combinatorial therapies aimed at sensitizing pancreatic cancer cells to chemotherapeutic agents as well as provide novel molecular mechanisms to better understand this phenomenon.
publishDate 2013
dc.date.none.fl_str_mv 2013-09
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/11336/11462
Gilabert, Mariana; Vaccaro, Maria Ines; Fernandez Zapico, Martín E.; Calvo, Ezequiel L.; Turrini, Olivier; et al.; Novel role of VMP1 as modifier of the pancreatic tumor cell response to chemotherapeutic drugs; Wiley; Journal of Cell Physiology; 228; 9; 9-2013; 1834-1843
1097-4652
url http://hdl.handle.net/11336/11462
identifier_str_mv Gilabert, Mariana; Vaccaro, Maria Ines; Fernandez Zapico, Martín E.; Calvo, Ezequiel L.; Turrini, Olivier; et al.; Novel role of VMP1 as modifier of the pancreatic tumor cell response to chemotherapeutic drugs; Wiley; Journal of Cell Physiology; 228; 9; 9-2013; 1834-1843
1097-4652
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048029/
info:eu-repo/semantics/altIdentifier/doi/
info:eu-repo/semantics/altIdentifier/doi/10.1002/jcp.24343
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
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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