Induction of apoptosis in human pancreatic cancer stem cells by the endoplasmic reticulum-targeted alkylphospholipid analog edelfosine and potentiation by autophagy inhibition

Autores
Gajate, Consuelo; Gayet, Odile; Fraunhoffer Navarro, Nicolas Alejandro; Iovanna, Juan Lucio; Dusetti, Nelson; Mollinedo, Faustino
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Pancreatic cancer is one of the most lethal malignancies with a poor and gloomy prognosis and the highest mortality-to-incidence ratio. Pancreatic cancer remains an incurable malignancy, and current therapies are ineffective. We isolated cancer stem cells (CSCs) from the human PANC-1 pancreatic cancer cell line as CD44+ CD24+ EpCAM+ cells. These CSCs form pancreatic cancer spheres or spheroids and develop tumors in SCID mice after subcutaneous injection of as few as 100 cells per mouse. Here, we found that the alkylphospholipid analog edelfosine inhibited CSC pancreatic cancer spheroid formation and induced cell death, as assessed by an increase in the percentage of cells in the sub-G0 /G1 region by means of flow cytometry, indicative of DNA breakdown and apoptosis. This correlated with an increase in caspase-3 activity and PARP breakdown, as a major substrate of caspase-3, following PANC-1 CSC treatment with edelfosine. The antitumor ether lipid edelfosine colocalized with the endoplasmic reticulum in both PANC-1 cells as well as PANC-1 CSCs by using a fluorescent edelfosine analog, and induced an endoplasmic reticulum stress response in both PANC-1 cells and PANC-1 CSCs, with a potent CHOP/GADD153 upregulation. Edelfosine elicited a strong autophagy response in both PANC-1 cells and PANC-1 CSCs, and preincubation of CSCs with autophagy inhibitors, chloroquine or bafilomycin A1, enhanced edelfosine-induced apoptosis. Primary cultures from pancreatic cancer patients were sensitive to edelfosine, as well as their respective isolated CSCs. Nontumorigenic pancreatic human cell line HPNE and normal human fibroblasts were largely spared. These data suggest that pancreatic CSCs isolated from established cell lines and pancreatic cancer patients are sensitive to edelfosine through its accumulation in the endoplasmic reticulum and induction of endoplasmic reticulum stress.
Fil: Gajate, Consuelo. Consejo Superior de Investigaciones Científicas. Centro de Investigaciones Biológicas; España. Universidad de Salamanca; España
Fil: Gayet, Odile. Centre National de la Recherche Scientifique; Francia
Fil: Fraunhoffer Navarro, Nicolas Alejandro. Centre National de la Recherche Scientifique; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina
Fil: Iovanna, Juan Lucio. Centre National de la Recherche Scientifique; Francia
Fil: Dusetti, Nelson. Centre National de la Recherche Scientifique; Francia
Fil: Mollinedo, Faustino. Consejo Superior de Investigaciones Científicas. Centro de Investigaciones Biológicas; España. Universidad de Salamanca; España
Materia
ALKYLPHOSPHOLIPID ANALOG
ANTITUMOR ETHER LIPID
AUTOPHAGY
EDELFOSINE
ENDO-PLASMIC RETICULUM TARGETING
ENDOPLASMIC RETICULUM
PANCREATIC CANCER
PANCREATIC CANCER SPHEROID
PANCREATIC CANCER STEM CELL
PRIMARY CULTURES FROM PANCREATIC CANCER PATIENTS
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:11336/212641
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/212641
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Induction of apoptosis in human pancreatic cancer stem cells by the endoplasmic reticulum-targeted alkylphospholipid analog edelfosine and potentiation by autophagy inhibitionGajate, ConsueloGayet, OdileFraunhoffer Navarro, Nicolas AlejandroIovanna, Juan LucioDusetti, NelsonMollinedo, FaustinoALKYLPHOSPHOLIPID ANALOGANTITUMOR ETHER LIPIDAUTOPHAGYEDELFOSINEENDO-PLASMIC RETICULUM TARGETINGENDOPLASMIC RETICULUMPANCREATIC CANCERPANCREATIC CANCER SPHEROIDPANCREATIC CANCER STEM CELLPRIMARY CULTURES FROM PANCREATIC CANCER PATIENTShttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Pancreatic cancer is one of the most lethal malignancies with a poor and gloomy prognosis and the highest mortality-to-incidence ratio. Pancreatic cancer remains an incurable malignancy, and current therapies are ineffective. We isolated cancer stem cells (CSCs) from the human PANC-1 pancreatic cancer cell line as CD44+ CD24+ EpCAM+ cells. These CSCs form pancreatic cancer spheres or spheroids and develop tumors in SCID mice after subcutaneous injection of as few as 100 cells per mouse. Here, we found that the alkylphospholipid analog edelfosine inhibited CSC pancreatic cancer spheroid formation and induced cell death, as assessed by an increase in the percentage of cells in the sub-G0 /G1 region by means of flow cytometry, indicative of DNA breakdown and apoptosis. This correlated with an increase in caspase-3 activity and PARP breakdown, as a major substrate of caspase-3, following PANC-1 CSC treatment with edelfosine. The antitumor ether lipid edelfosine colocalized with the endoplasmic reticulum in both PANC-1 cells as well as PANC-1 CSCs by using a fluorescent edelfosine analog, and induced an endoplasmic reticulum stress response in both PANC-1 cells and PANC-1 CSCs, with a potent CHOP/GADD153 upregulation. Edelfosine elicited a strong autophagy response in both PANC-1 cells and PANC-1 CSCs, and preincubation of CSCs with autophagy inhibitors, chloroquine or bafilomycin A1, enhanced edelfosine-induced apoptosis. Primary cultures from pancreatic cancer patients were sensitive to edelfosine, as well as their respective isolated CSCs. Nontumorigenic pancreatic human cell line HPNE and normal human fibroblasts were largely spared. These data suggest that pancreatic CSCs isolated from established cell lines and pancreatic cancer patients are sensitive to edelfosine through its accumulation in the endoplasmic reticulum and induction of endoplasmic reticulum stress.Fil: Gajate, Consuelo. Consejo Superior de Investigaciones Científicas. Centro de Investigaciones Biológicas; España. Universidad de Salamanca; EspañaFil: Gayet, Odile. Centre National de la Recherche Scientifique; FranciaFil: Fraunhoffer Navarro, Nicolas Alejandro. Centre National de la Recherche Scientifique; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Iovanna, Juan Lucio. Centre National de la Recherche Scientifique; FranciaFil: Dusetti, Nelson. Centre National de la Recherche Scientifique; FranciaFil: Mollinedo, Faustino. Consejo Superior de Investigaciones Científicas. Centro de Investigaciones Biológicas; España. Universidad de Salamanca; EspañaMDPI2021-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/212641Gajate, Consuelo; Gayet, Odile; Fraunhoffer Navarro, Nicolas Alejandro; Iovanna, Juan Lucio; Dusetti, Nelson; et al.; Induction of apoptosis in human pancreatic cancer stem cells by the endoplasmic reticulum-targeted alkylphospholipid analog edelfosine and potentiation by autophagy inhibition; MDPI; Cancers; 13; 23; 12-2021; 1-222072-6694CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.3390/cancers13236124info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:27:16Zoai:ri.conicet.gov.ar:11336/212641instacron: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:34982025-10-15 14:27:16.372CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Induction of apoptosis in human pancreatic cancer stem cells by the endoplasmic reticulum-targeted alkylphospholipid analog edelfosine and potentiation by autophagy inhibition
title Induction of apoptosis in human pancreatic cancer stem cells by the endoplasmic reticulum-targeted alkylphospholipid analog edelfosine and potentiation by autophagy inhibition
spellingShingle Induction of apoptosis in human pancreatic cancer stem cells by the endoplasmic reticulum-targeted alkylphospholipid analog edelfosine and potentiation by autophagy inhibition
Gajate, Consuelo
ALKYLPHOSPHOLIPID ANALOG
ANTITUMOR ETHER LIPID
AUTOPHAGY
EDELFOSINE
ENDO-PLASMIC RETICULUM TARGETING
ENDOPLASMIC RETICULUM
PANCREATIC CANCER
PANCREATIC CANCER SPHEROID
PANCREATIC CANCER STEM CELL
PRIMARY CULTURES FROM PANCREATIC CANCER PATIENTS
title_short Induction of apoptosis in human pancreatic cancer stem cells by the endoplasmic reticulum-targeted alkylphospholipid analog edelfosine and potentiation by autophagy inhibition
title_full Induction of apoptosis in human pancreatic cancer stem cells by the endoplasmic reticulum-targeted alkylphospholipid analog edelfosine and potentiation by autophagy inhibition
title_fullStr Induction of apoptosis in human pancreatic cancer stem cells by the endoplasmic reticulum-targeted alkylphospholipid analog edelfosine and potentiation by autophagy inhibition
title_full_unstemmed Induction of apoptosis in human pancreatic cancer stem cells by the endoplasmic reticulum-targeted alkylphospholipid analog edelfosine and potentiation by autophagy inhibition
title_sort Induction of apoptosis in human pancreatic cancer stem cells by the endoplasmic reticulum-targeted alkylphospholipid analog edelfosine and potentiation by autophagy inhibition
dc.creator.none.fl_str_mv Gajate, Consuelo
Gayet, Odile
Fraunhoffer Navarro, Nicolas Alejandro
Iovanna, Juan Lucio
Dusetti, Nelson
Mollinedo, Faustino
author Gajate, Consuelo
author_facet Gajate, Consuelo
Gayet, Odile
Fraunhoffer Navarro, Nicolas Alejandro
Iovanna, Juan Lucio
Dusetti, Nelson
Mollinedo, Faustino
author_role author
author2 Gayet, Odile
Fraunhoffer Navarro, Nicolas Alejandro
Iovanna, Juan Lucio
Dusetti, Nelson
Mollinedo, Faustino
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv ALKYLPHOSPHOLIPID ANALOG
ANTITUMOR ETHER LIPID
AUTOPHAGY
EDELFOSINE
ENDO-PLASMIC RETICULUM TARGETING
ENDOPLASMIC RETICULUM
PANCREATIC CANCER
PANCREATIC CANCER SPHEROID
PANCREATIC CANCER STEM CELL
PRIMARY CULTURES FROM PANCREATIC CANCER PATIENTS
topic ALKYLPHOSPHOLIPID ANALOG
ANTITUMOR ETHER LIPID
AUTOPHAGY
EDELFOSINE
ENDO-PLASMIC RETICULUM TARGETING
ENDOPLASMIC RETICULUM
PANCREATIC CANCER
PANCREATIC CANCER SPHEROID
PANCREATIC CANCER STEM CELL
PRIMARY CULTURES FROM PANCREATIC CANCER PATIENTS
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Pancreatic cancer is one of the most lethal malignancies with a poor and gloomy prognosis and the highest mortality-to-incidence ratio. Pancreatic cancer remains an incurable malignancy, and current therapies are ineffective. We isolated cancer stem cells (CSCs) from the human PANC-1 pancreatic cancer cell line as CD44+ CD24+ EpCAM+ cells. These CSCs form pancreatic cancer spheres or spheroids and develop tumors in SCID mice after subcutaneous injection of as few as 100 cells per mouse. Here, we found that the alkylphospholipid analog edelfosine inhibited CSC pancreatic cancer spheroid formation and induced cell death, as assessed by an increase in the percentage of cells in the sub-G0 /G1 region by means of flow cytometry, indicative of DNA breakdown and apoptosis. This correlated with an increase in caspase-3 activity and PARP breakdown, as a major substrate of caspase-3, following PANC-1 CSC treatment with edelfosine. The antitumor ether lipid edelfosine colocalized with the endoplasmic reticulum in both PANC-1 cells as well as PANC-1 CSCs by using a fluorescent edelfosine analog, and induced an endoplasmic reticulum stress response in both PANC-1 cells and PANC-1 CSCs, with a potent CHOP/GADD153 upregulation. Edelfosine elicited a strong autophagy response in both PANC-1 cells and PANC-1 CSCs, and preincubation of CSCs with autophagy inhibitors, chloroquine or bafilomycin A1, enhanced edelfosine-induced apoptosis. Primary cultures from pancreatic cancer patients were sensitive to edelfosine, as well as their respective isolated CSCs. Nontumorigenic pancreatic human cell line HPNE and normal human fibroblasts were largely spared. These data suggest that pancreatic CSCs isolated from established cell lines and pancreatic cancer patients are sensitive to edelfosine through its accumulation in the endoplasmic reticulum and induction of endoplasmic reticulum stress.
Fil: Gajate, Consuelo. Consejo Superior de Investigaciones Científicas. Centro de Investigaciones Biológicas; España. Universidad de Salamanca; España
Fil: Gayet, Odile. Centre National de la Recherche Scientifique; Francia
Fil: Fraunhoffer Navarro, Nicolas Alejandro. Centre National de la Recherche Scientifique; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina
Fil: Iovanna, Juan Lucio. Centre National de la Recherche Scientifique; Francia
Fil: Dusetti, Nelson. Centre National de la Recherche Scientifique; Francia
Fil: Mollinedo, Faustino. Consejo Superior de Investigaciones Científicas. Centro de Investigaciones Biológicas; España. Universidad de Salamanca; España
description Pancreatic cancer is one of the most lethal malignancies with a poor and gloomy prognosis and the highest mortality-to-incidence ratio. Pancreatic cancer remains an incurable malignancy, and current therapies are ineffective. We isolated cancer stem cells (CSCs) from the human PANC-1 pancreatic cancer cell line as CD44+ CD24+ EpCAM+ cells. These CSCs form pancreatic cancer spheres or spheroids and develop tumors in SCID mice after subcutaneous injection of as few as 100 cells per mouse. Here, we found that the alkylphospholipid analog edelfosine inhibited CSC pancreatic cancer spheroid formation and induced cell death, as assessed by an increase in the percentage of cells in the sub-G0 /G1 region by means of flow cytometry, indicative of DNA breakdown and apoptosis. This correlated with an increase in caspase-3 activity and PARP breakdown, as a major substrate of caspase-3, following PANC-1 CSC treatment with edelfosine. The antitumor ether lipid edelfosine colocalized with the endoplasmic reticulum in both PANC-1 cells as well as PANC-1 CSCs by using a fluorescent edelfosine analog, and induced an endoplasmic reticulum stress response in both PANC-1 cells and PANC-1 CSCs, with a potent CHOP/GADD153 upregulation. Edelfosine elicited a strong autophagy response in both PANC-1 cells and PANC-1 CSCs, and preincubation of CSCs with autophagy inhibitors, chloroquine or bafilomycin A1, enhanced edelfosine-induced apoptosis. Primary cultures from pancreatic cancer patients were sensitive to edelfosine, as well as their respective isolated CSCs. Nontumorigenic pancreatic human cell line HPNE and normal human fibroblasts were largely spared. These data suggest that pancreatic CSCs isolated from established cell lines and pancreatic cancer patients are sensitive to edelfosine through its accumulation in the endoplasmic reticulum and induction of endoplasmic reticulum stress.
publishDate 2021
dc.date.none.fl_str_mv 2021-12
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/11336/212641
Gajate, Consuelo; Gayet, Odile; Fraunhoffer Navarro, Nicolas Alejandro; Iovanna, Juan Lucio; Dusetti, Nelson; et al.; Induction of apoptosis in human pancreatic cancer stem cells by the endoplasmic reticulum-targeted alkylphospholipid analog edelfosine and potentiation by autophagy inhibition; MDPI; Cancers; 13; 23; 12-2021; 1-22
2072-6694
CONICET Digital
CONICET
url http://hdl.handle.net/11336/212641
identifier_str_mv Gajate, Consuelo; Gayet, Odile; Fraunhoffer Navarro, Nicolas Alejandro; Iovanna, Juan Lucio; Dusetti, Nelson; et al.; Induction of apoptosis in human pancreatic cancer stem cells by the endoplasmic reticulum-targeted alkylphospholipid analog edelfosine and potentiation by autophagy inhibition; MDPI; Cancers; 13; 23; 12-2021; 1-22
2072-6694
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.3390/cancers13236124
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 MDPI
publisher.none.fl_str_mv MDPI
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 13.22299

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