Vitamin D receptor and paclitaxel in triple negative breast cancer: is there a link bethween them?

Autores
Guevara, Josefina Alejandra; Ibarra, Agustina; Quevedo, Mario Alfredo; Alonso, Eliana Noelia; Colo, Georgina Pamela; Facchinetti, Maria Marta; Ferronato, María Julia; Curino, Alejandro Carlos
Año de publicación
2021
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Paclitaxel (PTX) is an antitumor agent employed in the treatment of Triple-Negative Breast Cancer (TNBC). TNBC expresses Vitamin D Receptor (VDR), a member of the nuclear receptor superfamily. The aim of this work was to investigate the involvement of VDR in the antitumor action of PTX in TNBC cells. To this end, viability assays by crystal violet staining were performed in murine 4T1 TNBC cells and in 4T1 stably expressing a shRNA against VDR (4T1 shVDR), treated with PTX (10 nM) or vehicle. Also, cell cycle was studied by flow cytometry. Cellular studies were complemented with in silico analyses including molecular docking and molecular dynamics (MD) simulations to describe the pharmacodynamic interaction between PTX and VDR. The results show that PTX reduced the viability of 4T1 wild type cells (p<0.001). These viability effects were lost in 4T1 shVDR cells which display approximately 53% of VDR levels with respect to control cells. Cell cycle analysis of 4T1 wild type and 4T1 shVDR cells treated with PTX showed that the chemotherapy causes an increase in the percentage of cells in sub G0/G1 phase compared to vehicle-treated cells. However, this PTX effect was significantly higher in wild type than in VDR-silenced cells (13.72 ± 2.37% vs 6.18 ± 1.07%, p<0.001). Docking and MD studies showed that PTX was not able to bind to the classical ligand-binding pocket of VDR. However, an exhaustive search of allosteric sites identified its stable binding to a cavity adjacent to the activating factor 2 (AF- 2) region. MD studies verified a conformational restraint on AF-2, which triggers transcriptional and antitumor effects. Furthermore, a potential cooperativity in the interaction with VDR between PTX and the natural ligand of the receptor was observed. Altogether, these results suggest that PTX could interact with VDR to display its anti- tumor effects in TNBC by its binding in an alternative site to that of the classical VDR agonists
Fil: Guevara, Josefina Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Ibarra, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Quevedo, Mario Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina
Fil: Alonso, Eliana Noelia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Colo, Georgina Pamela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Facchinetti, Maria Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Ferronato, María Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Curino, Alejandro Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
LXVI Reunión Anual de la Sociedad Argentina de Investigación Clínica ; LXIX Reunión anual de la Sociedad Argentina de Inmunología ; LIII Reunión Anual de la Asociación Argentina de Farmacología Experimental y XI Reunión Anual de la Asociación Argentina de Nanomedicinas
Buenos Aires
Argentina
Sociedad Argentina de Investigación Clínica
Sociedad Argentina de Inmunología
Asociación Argentina de Farmacología Experimental
Asociación Argentina de Nanomedicinas
Materia
Breast Cancer
Paclitaxel
VDR
Docking
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:11336/199651
Acceder
id CONICETDig_27ab1cb81d67acfe13b28c37abd168e5
oai_identifier_str oai:ri.conicet.gov.ar:11336/199651
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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Vitamin D receptor and paclitaxel in triple negative breast cancer: is there a link bethween them?Guevara, Josefina AlejandraIbarra, AgustinaQuevedo, Mario AlfredoAlonso, Eliana NoeliaColo, Georgina PamelaFacchinetti, Maria MartaFerronato, María JuliaCurino, Alejandro CarlosBreast CancerPaclitaxelVDRDockinghttps://purl.org/becyt/ford/3.5https://purl.org/becyt/ford/3Paclitaxel (PTX) is an antitumor agent employed in the treatment of Triple-Negative Breast Cancer (TNBC). TNBC expresses Vitamin D Receptor (VDR), a member of the nuclear receptor superfamily. The aim of this work was to investigate the involvement of VDR in the antitumor action of PTX in TNBC cells. To this end, viability assays by crystal violet staining were performed in murine 4T1 TNBC cells and in 4T1 stably expressing a shRNA against VDR (4T1 shVDR), treated with PTX (10 nM) or vehicle. Also, cell cycle was studied by flow cytometry. Cellular studies were complemented with in silico analyses including molecular docking and molecular dynamics (MD) simulations to describe the pharmacodynamic interaction between PTX and VDR. The results show that PTX reduced the viability of 4T1 wild type cells (p<0.001). These viability effects were lost in 4T1 shVDR cells which display approximately 53% of VDR levels with respect to control cells. Cell cycle analysis of 4T1 wild type and 4T1 shVDR cells treated with PTX showed that the chemotherapy causes an increase in the percentage of cells in sub G0/G1 phase compared to vehicle-treated cells. However, this PTX effect was significantly higher in wild type than in VDR-silenced cells (13.72 ± 2.37% vs 6.18 ± 1.07%, p<0.001). Docking and MD studies showed that PTX was not able to bind to the classical ligand-binding pocket of VDR. However, an exhaustive search of allosteric sites identified its stable binding to a cavity adjacent to the activating factor 2 (AF- 2) region. MD studies verified a conformational restraint on AF-2, which triggers transcriptional and antitumor effects. Furthermore, a potential cooperativity in the interaction with VDR between PTX and the natural ligand of the receptor was observed. Altogether, these results suggest that PTX could interact with VDR to display its anti- tumor effects in TNBC by its binding in an alternative site to that of the classical VDR agonistsFil: Guevara, Josefina Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Ibarra, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Quevedo, Mario Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; ArgentinaFil: Alonso, Eliana Noelia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Colo, Georgina Pamela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Facchinetti, Maria Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Ferronato, María Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Curino, Alejandro Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaLXVI Reunión Anual de la Sociedad Argentina de Investigación Clínica ; LXIX Reunión anual de la Sociedad Argentina de Inmunología ; LIII Reunión Anual de la Asociación Argentina de Farmacología Experimental y XI Reunión Anual de la Asociación Argentina de NanomedicinasBuenos AiresArgentinaSociedad Argentina de Investigación ClínicaSociedad Argentina de InmunologíaAsociación Argentina de Farmacología ExperimentalAsociación Argentina de NanomedicinasFundación Revista MedicinaKotsias, Basilio Aristidesde Vito, EduardoNarvaiz Kantor, IsabelLüthy, Isabel2021info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectReuniónJournalhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/199651Vitamin D receptor and paclitaxel in triple negative breast cancer: is there a link bethween them?; LXVI Reunión Anual de la Sociedad Argentina de Investigación Clínica ; LXIX Reunión anual de la Sociedad Argentina de Inmunología ; LIII Reunión Anual de la Asociación Argentina de Farmacología Experimental y XI Reunión Anual de la Asociación Argentina de Nanomedicinas; Buenos Aires; Argentina; 2021; 221-2210025-76801669-9106CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.saic.org.ar/revista-medicinaNacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:00:31Zoai:ri.conicet.gov.ar:11336/199651instacron: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 10:00:32.106CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Vitamin D receptor and paclitaxel in triple negative breast cancer: is there a link bethween them?
title Vitamin D receptor and paclitaxel in triple negative breast cancer: is there a link bethween them?
spellingShingle Vitamin D receptor and paclitaxel in triple negative breast cancer: is there a link bethween them?
Guevara, Josefina Alejandra
Breast Cancer
Paclitaxel
VDR
Docking
title_short Vitamin D receptor and paclitaxel in triple negative breast cancer: is there a link bethween them?
title_full Vitamin D receptor and paclitaxel in triple negative breast cancer: is there a link bethween them?
title_fullStr Vitamin D receptor and paclitaxel in triple negative breast cancer: is there a link bethween them?
title_full_unstemmed Vitamin D receptor and paclitaxel in triple negative breast cancer: is there a link bethween them?
title_sort Vitamin D receptor and paclitaxel in triple negative breast cancer: is there a link bethween them?
dc.creator.none.fl_str_mv Guevara, Josefina Alejandra
Ibarra, Agustina
Quevedo, Mario Alfredo
Alonso, Eliana Noelia
Colo, Georgina Pamela
Facchinetti, Maria Marta
Ferronato, María Julia
Curino, Alejandro Carlos
author Guevara, Josefina Alejandra
author_facet Guevara, Josefina Alejandra
Ibarra, Agustina
Quevedo, Mario Alfredo
Alonso, Eliana Noelia
Colo, Georgina Pamela
Facchinetti, Maria Marta
Ferronato, María Julia
Curino, Alejandro Carlos
author_role author
author2 Ibarra, Agustina
Quevedo, Mario Alfredo
Alonso, Eliana Noelia
Colo, Georgina Pamela
Facchinetti, Maria Marta
Ferronato, María Julia
Curino, Alejandro Carlos
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Kotsias, Basilio Aristides
de Vito, Eduardo
Narvaiz Kantor, Isabel
Lüthy, Isabel
dc.subject.none.fl_str_mv Breast Cancer
Paclitaxel
VDR
Docking
topic Breast Cancer
Paclitaxel
VDR
Docking
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.5
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Paclitaxel (PTX) is an antitumor agent employed in the treatment of Triple-Negative Breast Cancer (TNBC). TNBC expresses Vitamin D Receptor (VDR), a member of the nuclear receptor superfamily. The aim of this work was to investigate the involvement of VDR in the antitumor action of PTX in TNBC cells. To this end, viability assays by crystal violet staining were performed in murine 4T1 TNBC cells and in 4T1 stably expressing a shRNA against VDR (4T1 shVDR), treated with PTX (10 nM) or vehicle. Also, cell cycle was studied by flow cytometry. Cellular studies were complemented with in silico analyses including molecular docking and molecular dynamics (MD) simulations to describe the pharmacodynamic interaction between PTX and VDR. The results show that PTX reduced the viability of 4T1 wild type cells (p<0.001). These viability effects were lost in 4T1 shVDR cells which display approximately 53% of VDR levels with respect to control cells. Cell cycle analysis of 4T1 wild type and 4T1 shVDR cells treated with PTX showed that the chemotherapy causes an increase in the percentage of cells in sub G0/G1 phase compared to vehicle-treated cells. However, this PTX effect was significantly higher in wild type than in VDR-silenced cells (13.72 ± 2.37% vs 6.18 ± 1.07%, p<0.001). Docking and MD studies showed that PTX was not able to bind to the classical ligand-binding pocket of VDR. However, an exhaustive search of allosteric sites identified its stable binding to a cavity adjacent to the activating factor 2 (AF- 2) region. MD studies verified a conformational restraint on AF-2, which triggers transcriptional and antitumor effects. Furthermore, a potential cooperativity in the interaction with VDR between PTX and the natural ligand of the receptor was observed. Altogether, these results suggest that PTX could interact with VDR to display its anti- tumor effects in TNBC by its binding in an alternative site to that of the classical VDR agonists
Fil: Guevara, Josefina Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Ibarra, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Quevedo, Mario Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina
Fil: Alonso, Eliana Noelia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Colo, Georgina Pamela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Facchinetti, Maria Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Ferronato, María Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Curino, Alejandro Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
LXVI Reunión Anual de la Sociedad Argentina de Investigación Clínica ; LXIX Reunión anual de la Sociedad Argentina de Inmunología ; LIII Reunión Anual de la Asociación Argentina de Farmacología Experimental y XI Reunión Anual de la Asociación Argentina de Nanomedicinas
Buenos Aires
Argentina
Sociedad Argentina de Investigación Clínica
Sociedad Argentina de Inmunología
Asociación Argentina de Farmacología Experimental
Asociación Argentina de Nanomedicinas
description Paclitaxel (PTX) is an antitumor agent employed in the treatment of Triple-Negative Breast Cancer (TNBC). TNBC expresses Vitamin D Receptor (VDR), a member of the nuclear receptor superfamily. The aim of this work was to investigate the involvement of VDR in the antitumor action of PTX in TNBC cells. To this end, viability assays by crystal violet staining were performed in murine 4T1 TNBC cells and in 4T1 stably expressing a shRNA against VDR (4T1 shVDR), treated with PTX (10 nM) or vehicle. Also, cell cycle was studied by flow cytometry. Cellular studies were complemented with in silico analyses including molecular docking and molecular dynamics (MD) simulations to describe the pharmacodynamic interaction between PTX and VDR. The results show that PTX reduced the viability of 4T1 wild type cells (p<0.001). These viability effects were lost in 4T1 shVDR cells which display approximately 53% of VDR levels with respect to control cells. Cell cycle analysis of 4T1 wild type and 4T1 shVDR cells treated with PTX showed that the chemotherapy causes an increase in the percentage of cells in sub G0/G1 phase compared to vehicle-treated cells. However, this PTX effect was significantly higher in wild type than in VDR-silenced cells (13.72 ± 2.37% vs 6.18 ± 1.07%, p<0.001). Docking and MD studies showed that PTX was not able to bind to the classical ligand-binding pocket of VDR. However, an exhaustive search of allosteric sites identified its stable binding to a cavity adjacent to the activating factor 2 (AF- 2) region. MD studies verified a conformational restraint on AF-2, which triggers transcriptional and antitumor effects. Furthermore, a potential cooperativity in the interaction with VDR between PTX and the natural ligand of the receptor was observed. Altogether, these results suggest that PTX could interact with VDR to display its anti- tumor effects in TNBC by its binding in an alternative site to that of the classical VDR agonists
publishDate 2021
dc.date.none.fl_str_mv 2021
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http://purl.org/coar/resource_type/c_5794
info:ar-repo/semantics/documentoDeConferencia
status_str publishedVersion
format conferenceObject
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/199651
Vitamin D receptor and paclitaxel in triple negative breast cancer: is there a link bethween them?; LXVI Reunión Anual de la Sociedad Argentina de Investigación Clínica ; LXIX Reunión anual de la Sociedad Argentina de Inmunología ; LIII Reunión Anual de la Asociación Argentina de Farmacología Experimental y XI Reunión Anual de la Asociación Argentina de Nanomedicinas; Buenos Aires; Argentina; 2021; 221-221
0025-7680
1669-9106
CONICET Digital
CONICET
url http://hdl.handle.net/11336/199651
identifier_str_mv Vitamin D receptor and paclitaxel in triple negative breast cancer: is there a link bethween them?; LXVI Reunión Anual de la Sociedad Argentina de Investigación Clínica ; LXIX Reunión anual de la Sociedad Argentina de Inmunología ; LIII Reunión Anual de la Asociación Argentina de Farmacología Experimental y XI Reunión Anual de la Asociación Argentina de Nanomedicinas; Buenos Aires; Argentina; 2021; 221-221
0025-7680
1669-9106
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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application/pdf
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dc.coverage.none.fl_str_mv Nacional
dc.publisher.none.fl_str_mv Fundación Revista Medicina
publisher.none.fl_str_mv Fundación Revista Medicina
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repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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