Acyl-CoA synthetase-4, a new regulator of mTOR and a potential therapeutic target for enhanced estrogen receptor function in receptor-positive and -negative breast cancer

Autores
Orlando, Ulises Daniel; Castillo, Ana Fernanda; Dattilo, Melina A.; Solano, Angela Rosario; Maloberti, Paula Mariana; Podesta, Ernesto Jorge
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Although the role of acyl-CoA synthetase 4 (ACSL4) in mediating an aggressive phenotype is well accepted, there is little evidence as to the early steps through which ACSL4 increases tumor growth and progression. In this study, and by means of the stable transfection of MCF-7 cells with ACSL4 using the tetracycline Tet-Off system (MCF-7 TetOff/ACSL4), we identify the mTOR pathway as one of the main specific signatures of ACSL4 expression and demonstrate the partial involvement of the lipoxygenase pathway in the activation of mTOR. The specificity of ACSL4 action on mTOR signaling is also determined by doxycycline inhibition of ACSL4 expression in MCF-7 Tet-Off/ACSL4 cells, by the expression of ACSL4 in the non-aggressive T47D breast cancer cell line and by knocking down this enzyme expression in the MDA-MB-231 breast cancer cells, which constitutively express ACSL4. ACSL4 regulates components of the two complexes of the mTOR pathway (mTORC1/2), along with upstream regulators and substrates. We show that mTOR inhibitor rapamycin and ACSL4 inhibitor rosiglitazone can act in combination to inhibit cell growth. In addition, we demonstrate a synergistic effect on cell growth inhibition by the combination of rosiglitazone and tamoxifen, an estrogen receptor α (ERα) inhibitor. Remarkably, this synergistic effect is also evident in the triple negative MDA-MB-231 cells in vitro and in vivo. These results suggest that ACSL4 could be a target to restore tumor hormone dependence in tumors with poor prognosis for disease-free and overall survival, in which no effective specifically targeted therapy is readily available.
Fil: Orlando, Ulises Daniel. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Castillo, Ana Fernanda. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Dattilo, Melina A.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina
Fil: Solano, Angela Rosario. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Maloberti, Paula Mariana. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Podesta, Ernesto Jorge. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Materia
ACSL4
BREAST CANCER
MTOR
TRANSCRIPTOMA
ARACHIDONIC ACID
CANCER
CELL SIGNALING
GENE EXPRESSION
TAMOXIFEN
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:11336/15347

id CONICETDig_90db48be553c5854a4ee9528941c9636
oai_identifier_str oai:ri.conicet.gov.ar:11336/15347
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Acyl-CoA synthetase-4, a new regulator of mTOR and a potential therapeutic target for enhanced estrogen receptor function in receptor-positive and -negative breast cancerOrlando, Ulises DanielCastillo, Ana FernandaDattilo, Melina A.Solano, Angela RosarioMaloberti, Paula MarianaPodesta, Ernesto JorgeACSL4BREAST CANCERMTORTRANSCRIPTOMAARACHIDONIC ACIDCANCERCELL SIGNALINGGENE EXPRESSIONTAMOXIFENhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Although the role of acyl-CoA synthetase 4 (ACSL4) in mediating an aggressive phenotype is well accepted, there is little evidence as to the early steps through which ACSL4 increases tumor growth and progression. In this study, and by means of the stable transfection of MCF-7 cells with ACSL4 using the tetracycline Tet-Off system (MCF-7 TetOff/ACSL4), we identify the mTOR pathway as one of the main specific signatures of ACSL4 expression and demonstrate the partial involvement of the lipoxygenase pathway in the activation of mTOR. The specificity of ACSL4 action on mTOR signaling is also determined by doxycycline inhibition of ACSL4 expression in MCF-7 Tet-Off/ACSL4 cells, by the expression of ACSL4 in the non-aggressive T47D breast cancer cell line and by knocking down this enzyme expression in the MDA-MB-231 breast cancer cells, which constitutively express ACSL4. ACSL4 regulates components of the two complexes of the mTOR pathway (mTORC1/2), along with upstream regulators and substrates. We show that mTOR inhibitor rapamycin and ACSL4 inhibitor rosiglitazone can act in combination to inhibit cell growth. In addition, we demonstrate a synergistic effect on cell growth inhibition by the combination of rosiglitazone and tamoxifen, an estrogen receptor α (ERα) inhibitor. Remarkably, this synergistic effect is also evident in the triple negative MDA-MB-231 cells in vitro and in vivo. These results suggest that ACSL4 could be a target to restore tumor hormone dependence in tumors with poor prognosis for disease-free and overall survival, in which no effective specifically targeted therapy is readily available.Fil: Orlando, Ulises Daniel. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Castillo, Ana Fernanda. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Dattilo, Melina A.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; ArgentinaFil: Solano, Angela Rosario. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Maloberti, Paula Mariana. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Podesta, Ernesto Jorge. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaImpact journals2015-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/15347Orlando, Ulises Daniel; Castillo, Ana Fernanda; Dattilo, Melina A.; Solano, Angela Rosario; Maloberti, Paula Mariana; et al.; Acyl-CoA synthetase-4, a new regulator of mTOR and a potential therapeutic target for enhanced estrogen receptor function in receptor-positive and -negative breast cancer; Impact journals; Oncotarget; 6; 40; 10-2015; 42632-426501949-2553enginfo:eu-repo/semantics/altIdentifier/url/http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=5822info:eu-repo/semantics/altIdentifier/doi/10.18632/oncotarget.5822info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:40:31Zoai:ri.conicet.gov.ar:11336/15347instacron: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 14:40:31.401CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Acyl-CoA synthetase-4, a new regulator of mTOR and a potential therapeutic target for enhanced estrogen receptor function in receptor-positive and -negative breast cancer
title Acyl-CoA synthetase-4, a new regulator of mTOR and a potential therapeutic target for enhanced estrogen receptor function in receptor-positive and -negative breast cancer
spellingShingle Acyl-CoA synthetase-4, a new regulator of mTOR and a potential therapeutic target for enhanced estrogen receptor function in receptor-positive and -negative breast cancer
Orlando, Ulises Daniel
ACSL4
BREAST CANCER
MTOR
TRANSCRIPTOMA
ARACHIDONIC ACID
CANCER
CELL SIGNALING
GENE EXPRESSION
TAMOXIFEN
title_short Acyl-CoA synthetase-4, a new regulator of mTOR and a potential therapeutic target for enhanced estrogen receptor function in receptor-positive and -negative breast cancer
title_full Acyl-CoA synthetase-4, a new regulator of mTOR and a potential therapeutic target for enhanced estrogen receptor function in receptor-positive and -negative breast cancer
title_fullStr Acyl-CoA synthetase-4, a new regulator of mTOR and a potential therapeutic target for enhanced estrogen receptor function in receptor-positive and -negative breast cancer
title_full_unstemmed Acyl-CoA synthetase-4, a new regulator of mTOR and a potential therapeutic target for enhanced estrogen receptor function in receptor-positive and -negative breast cancer
title_sort Acyl-CoA synthetase-4, a new regulator of mTOR and a potential therapeutic target for enhanced estrogen receptor function in receptor-positive and -negative breast cancer
dc.creator.none.fl_str_mv Orlando, Ulises Daniel
Castillo, Ana Fernanda
Dattilo, Melina A.
Solano, Angela Rosario
Maloberti, Paula Mariana
Podesta, Ernesto Jorge
author Orlando, Ulises Daniel
author_facet Orlando, Ulises Daniel
Castillo, Ana Fernanda
Dattilo, Melina A.
Solano, Angela Rosario
Maloberti, Paula Mariana
Podesta, Ernesto Jorge
author_role author
author2 Castillo, Ana Fernanda
Dattilo, Melina A.
Solano, Angela Rosario
Maloberti, Paula Mariana
Podesta, Ernesto Jorge
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv ACSL4
BREAST CANCER
MTOR
TRANSCRIPTOMA
ARACHIDONIC ACID
CANCER
CELL SIGNALING
GENE EXPRESSION
TAMOXIFEN
topic ACSL4
BREAST CANCER
MTOR
TRANSCRIPTOMA
ARACHIDONIC ACID
CANCER
CELL SIGNALING
GENE EXPRESSION
TAMOXIFEN
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Although the role of acyl-CoA synthetase 4 (ACSL4) in mediating an aggressive phenotype is well accepted, there is little evidence as to the early steps through which ACSL4 increases tumor growth and progression. In this study, and by means of the stable transfection of MCF-7 cells with ACSL4 using the tetracycline Tet-Off system (MCF-7 TetOff/ACSL4), we identify the mTOR pathway as one of the main specific signatures of ACSL4 expression and demonstrate the partial involvement of the lipoxygenase pathway in the activation of mTOR. The specificity of ACSL4 action on mTOR signaling is also determined by doxycycline inhibition of ACSL4 expression in MCF-7 Tet-Off/ACSL4 cells, by the expression of ACSL4 in the non-aggressive T47D breast cancer cell line and by knocking down this enzyme expression in the MDA-MB-231 breast cancer cells, which constitutively express ACSL4. ACSL4 regulates components of the two complexes of the mTOR pathway (mTORC1/2), along with upstream regulators and substrates. We show that mTOR inhibitor rapamycin and ACSL4 inhibitor rosiglitazone can act in combination to inhibit cell growth. In addition, we demonstrate a synergistic effect on cell growth inhibition by the combination of rosiglitazone and tamoxifen, an estrogen receptor α (ERα) inhibitor. Remarkably, this synergistic effect is also evident in the triple negative MDA-MB-231 cells in vitro and in vivo. These results suggest that ACSL4 could be a target to restore tumor hormone dependence in tumors with poor prognosis for disease-free and overall survival, in which no effective specifically targeted therapy is readily available.
Fil: Orlando, Ulises Daniel. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Castillo, Ana Fernanda. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Dattilo, Melina A.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina
Fil: Solano, Angela Rosario. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Maloberti, Paula Mariana. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Podesta, Ernesto Jorge. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
description Although the role of acyl-CoA synthetase 4 (ACSL4) in mediating an aggressive phenotype is well accepted, there is little evidence as to the early steps through which ACSL4 increases tumor growth and progression. In this study, and by means of the stable transfection of MCF-7 cells with ACSL4 using the tetracycline Tet-Off system (MCF-7 TetOff/ACSL4), we identify the mTOR pathway as one of the main specific signatures of ACSL4 expression and demonstrate the partial involvement of the lipoxygenase pathway in the activation of mTOR. The specificity of ACSL4 action on mTOR signaling is also determined by doxycycline inhibition of ACSL4 expression in MCF-7 Tet-Off/ACSL4 cells, by the expression of ACSL4 in the non-aggressive T47D breast cancer cell line and by knocking down this enzyme expression in the MDA-MB-231 breast cancer cells, which constitutively express ACSL4. ACSL4 regulates components of the two complexes of the mTOR pathway (mTORC1/2), along with upstream regulators and substrates. We show that mTOR inhibitor rapamycin and ACSL4 inhibitor rosiglitazone can act in combination to inhibit cell growth. In addition, we demonstrate a synergistic effect on cell growth inhibition by the combination of rosiglitazone and tamoxifen, an estrogen receptor α (ERα) inhibitor. Remarkably, this synergistic effect is also evident in the triple negative MDA-MB-231 cells in vitro and in vivo. These results suggest that ACSL4 could be a target to restore tumor hormone dependence in tumors with poor prognosis for disease-free and overall survival, in which no effective specifically targeted therapy is readily available.
publishDate 2015
dc.date.none.fl_str_mv 2015-10
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/11336/15347
Orlando, Ulises Daniel; Castillo, Ana Fernanda; Dattilo, Melina A.; Solano, Angela Rosario; Maloberti, Paula Mariana; et al.; Acyl-CoA synthetase-4, a new regulator of mTOR and a potential therapeutic target for enhanced estrogen receptor function in receptor-positive and -negative breast cancer; Impact journals; Oncotarget; 6; 40; 10-2015; 42632-42650
1949-2553
url http://hdl.handle.net/11336/15347
identifier_str_mv Orlando, Ulises Daniel; Castillo, Ana Fernanda; Dattilo, Melina A.; Solano, Angela Rosario; Maloberti, Paula Mariana; et al.; Acyl-CoA synthetase-4, a new regulator of mTOR and a potential therapeutic target for enhanced estrogen receptor function in receptor-positive and -negative breast cancer; Impact journals; Oncotarget; 6; 40; 10-2015; 42632-42650
1949-2553
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=5822
info:eu-repo/semantics/altIdentifier/doi/10.18632/oncotarget.5822
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 Impact journals
publisher.none.fl_str_mv Impact journals
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
_version_ 1846082897441718272
score 13.22299