Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum

Pancreatic cancer remains as one of the most deadly cancers, and responds poorly to current therapies. The prognosis is extremely poor, with a 5-year survival of less than 5%. Therefore, search for new effective therapeutic drugs is of pivotal need and urgency to improve treatment of this incurable...

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Autores: Gajate, Consuelo, Matos-da-Silva, Marcia, Dakir, El Habib, Fonteriz, Rosalba I., Álvarez, Javier, Mollinedo, Faustino
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2011
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/51135
Acceso en línea:http://hdl.handle.net/10261/51135
Access Level:acceso abierto
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spelling Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulumGajate, ConsueloMatos-da-Silva, MarciaDakir, El HabibFonteriz, Rosalba I.Álvarez, JavierMollinedo, FaustinoPancreatic cancer remains as one of the most deadly cancers, and responds poorly to current therapies. The prognosis is extremely poor, with a 5-year survival of less than 5%. Therefore, search for new effective therapeutic drugs is of pivotal need and urgency to improve treatment of this incurable malignancy. Synthetic alkyl-lysophospholipid analogs (ALPs) constitute a heterogeneous group of unnatural lipids that promote apoptosis in a wide variety of tumor cells. In this study, we found that the anticancer drug edelfosine was the most potent ALP in killing human pancreatic cancer cells, targeting endoplasmic reticulum (ER). Edelfosine was taken up in significant amounts by pancreatic cancer cells and induced caspase- and mitochondrial-mediated apoptosis. Pancreatic cancer cells show a prominent ER and edelfosine accumulated in this subcellular structure, inducing a potent ER stress response, with caspase-4, BAP31 and c-Jun NH2-terminal kinase (JNK) activation, CHOP/GADD153 upregulation and phosphorylation of eukaryotic translation initiation factor 2 α-subunit that eventually led to cell death. Oral administration of edelfosine in xenograft mouse models of pancreatic cancer induced a significant regression in tumor growth and an increase in apoptotic index, as assessed by TUNEL assay and caspase-3 activation in the tumor sections. The ER stress-associated marker CHOP/GADD153 was visualized in the pancreatic tumor isolated from edelfosine-treated mice, indicating a strong in vivo ER stress response. These results suggest that edelfosine exerts its pro-apoptotic action in pancreatic cancer cells, both in vitro and in vivo, through its accumulation in the ER, which leads to ER stress and apoptosis. Thus, we propose that the ER could be a key target in pancreatic cancer, and edelfosine may constitute a prototype for the development of a new class of antitumor drugs targeting the ER.This work was supported by grants from Fondo de Investigación Sanitaria and European Commission (FIS-FEDER PS09/ 01915), Ministerio de Ciencia e Innovación (SAF2008-02251, BFU 2008-01871 and RD06/0020/1037 from Red Temática de Investigación Cooperativa en Cáncer, Instituto de Salud Carlos III), European Community’s Seventh Framework Programme FP7-2007-2013 (Grant HEALTH-F2-2011-256986) and Junta de Castilla y León (CSI052A11-2, GR15-Experimental Therapeutics and Translational Oncology Program, Biomedicine Project 2009 and Biomedicine Project 2010-2011). CG is supported by the Ramón y Cajal Program from the Ministerio de Ciencia e Innovación of Spain.Peer ReviewedNature Publishing GroupEuropean CommissionMinisterio de Ciencia e Innovación (España)Junta de Castilla y LeónInstituto de Salud Carlos IIIInstituto de Salud Carlos IIIRed Temática de Investigación Cooperativa en Cáncer (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2012201220112012info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersionhttp://hdl.handle.net/10261/51135reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/EC/FP7/256986http://dx.doi.org/10.1038/onc.2011.446Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/511352026-05-22T06:33:51Z
dc.title.none.fl_str_mv Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum
title Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum
spellingShingle Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum
Gajate, Consuelo
title_short Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum
title_full Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum
title_fullStr Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum
title_full_unstemmed Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum
title_sort Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum
dc.creator.none.fl_str_mv Gajate, Consuelo
Matos-da-Silva, Marcia
Dakir, El Habib
Fonteriz, Rosalba I.
Álvarez, Javier
Mollinedo, Faustino
author Gajate, Consuelo
author_facet Gajate, Consuelo
Matos-da-Silva, Marcia
Dakir, El Habib
Fonteriz, Rosalba I.
Álvarez, Javier
Mollinedo, Faustino
author_role author
author2 Matos-da-Silva, Marcia
Dakir, El Habib
Fonteriz, Rosalba I.
Álvarez, Javier
Mollinedo, Faustino
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv European Commission
Ministerio de Ciencia e Innovación (España)
Junta de Castilla y León
Instituto de Salud Carlos III
Instituto de Salud Carlos III
Red Temática de Investigación Cooperativa en Cáncer (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
description Pancreatic cancer remains as one of the most deadly cancers, and responds poorly to current therapies. The prognosis is extremely poor, with a 5-year survival of less than 5%. Therefore, search for new effective therapeutic drugs is of pivotal need and urgency to improve treatment of this incurable malignancy. Synthetic alkyl-lysophospholipid analogs (ALPs) constitute a heterogeneous group of unnatural lipids that promote apoptosis in a wide variety of tumor cells. In this study, we found that the anticancer drug edelfosine was the most potent ALP in killing human pancreatic cancer cells, targeting endoplasmic reticulum (ER). Edelfosine was taken up in significant amounts by pancreatic cancer cells and induced caspase- and mitochondrial-mediated apoptosis. Pancreatic cancer cells show a prominent ER and edelfosine accumulated in this subcellular structure, inducing a potent ER stress response, with caspase-4, BAP31 and c-Jun NH2-terminal kinase (JNK) activation, CHOP/GADD153 upregulation and phosphorylation of eukaryotic translation initiation factor 2 α-subunit that eventually led to cell death. Oral administration of edelfosine in xenograft mouse models of pancreatic cancer induced a significant regression in tumor growth and an increase in apoptotic index, as assessed by TUNEL assay and caspase-3 activation in the tumor sections. The ER stress-associated marker CHOP/GADD153 was visualized in the pancreatic tumor isolated from edelfosine-treated mice, indicating a strong in vivo ER stress response. These results suggest that edelfosine exerts its pro-apoptotic action in pancreatic cancer cells, both in vitro and in vivo, through its accumulation in the ER, which leads to ER stress and apoptosis. Thus, we propose that the ER could be a key target in pancreatic cancer, and edelfosine may constitute a prototype for the development of a new class of antitumor drugs targeting the ER.
publishDate 2011
dc.date.none.fl_str_mv 2011
2012
2012
2012
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
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info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/51135
url http://hdl.handle.net/10261/51135
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/EC/FP7/256986
http://dx.doi.org/10.1038/onc.2011.446
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
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