A progesterone derivative linked to a stable phospholipid activates breast cancer cell response without leaving the cell membrane

In hormone-responsive breast cancer cells, progesterone (P4) has been shown to act via its nuclear receptor (nPR), a ligand-activated transcription factor. A small fraction of progesterone receptor is palmitoylated and anchored to the cell membrane (mbPR) forming a complex with estrogen receptor alp...

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Detalles Bibliográficos
Autores: Font Mateu, Jofre, 1977-, Sanllehí, Pol, Sot, Jesús, Abad, Beatriz, Mateos, Nicolas, Torreno-Pina, Juan A., Ferrari, Roberto, Wright, Roni H.G., Garcia-Parajo, Maria F., Joglar Tamargo, Jesús, Goñi, Félix M., Beato, Miguel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/60809
Acceso en línea:http://hdl.handle.net/10230/60809
http://dx.doi.org/10.1007/s00018-024-05116-3
Access Level:acceso abierto
Palabra clave:Breast cancer cells
Cell membrane phospholipids
Nuclear hormone receptors
Progesterone receptor
Progesterone signaling
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oai_identifier_str oai:recercat.cat:10230/60809
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv A progesterone derivative linked to a stable phospholipid activates breast cancer cell response without leaving the cell membrane
title A progesterone derivative linked to a stable phospholipid activates breast cancer cell response without leaving the cell membrane
spellingShingle A progesterone derivative linked to a stable phospholipid activates breast cancer cell response without leaving the cell membrane
Font Mateu, Jofre, 1977-
Breast cancer cells
Cell membrane phospholipids
Nuclear hormone receptors
Progesterone receptor
Progesterone signaling
title_short A progesterone derivative linked to a stable phospholipid activates breast cancer cell response without leaving the cell membrane
title_full A progesterone derivative linked to a stable phospholipid activates breast cancer cell response without leaving the cell membrane
title_fullStr A progesterone derivative linked to a stable phospholipid activates breast cancer cell response without leaving the cell membrane
title_full_unstemmed A progesterone derivative linked to a stable phospholipid activates breast cancer cell response without leaving the cell membrane
title_sort A progesterone derivative linked to a stable phospholipid activates breast cancer cell response without leaving the cell membrane
dc.creator.none.fl_str_mv Font Mateu, Jofre, 1977-
Sanllehí, Pol
Sot, Jesús
Abad, Beatriz
Mateos, Nicolas
Torreno-Pina, Juan A.
Ferrari, Roberto
Wright, Roni H.G.
Garcia-Parajo, Maria F.
Joglar Tamargo, Jesús
Goñi, Félix M.
Beato, Miguel
author Font Mateu, Jofre, 1977-
author_facet Font Mateu, Jofre, 1977-
Sanllehí, Pol
Sot, Jesús
Abad, Beatriz
Mateos, Nicolas
Torreno-Pina, Juan A.
Ferrari, Roberto
Wright, Roni H.G.
Garcia-Parajo, Maria F.
Joglar Tamargo, Jesús
Goñi, Félix M.
Beato, Miguel
author_role author
author2 Sanllehí, Pol
Sot, Jesús
Abad, Beatriz
Mateos, Nicolas
Torreno-Pina, Juan A.
Ferrari, Roberto
Wright, Roni H.G.
Garcia-Parajo, Maria F.
Joglar Tamargo, Jesús
Goñi, Félix M.
Beato, Miguel
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Breast cancer cells
Cell membrane phospholipids
Nuclear hormone receptors
Progesterone receptor
Progesterone signaling
topic Breast cancer cells
Cell membrane phospholipids
Nuclear hormone receptors
Progesterone receptor
Progesterone signaling
description In hormone-responsive breast cancer cells, progesterone (P4) has been shown to act via its nuclear receptor (nPR), a ligand-activated transcription factor. A small fraction of progesterone receptor is palmitoylated and anchored to the cell membrane (mbPR) forming a complex with estrogen receptor alpha (ERα). Upon hormone exposure, either directly or via interaction with ERα, mbPR activates the SRC/RAS/ERK kinase pathway leading to phosphorylation of nPR by ERK. Kinase activation is essential for P4 gene regulation, as the ERK and MSK1 kinases are recruited by the nPR to its genomic binding sites and trigger chromatin remodeling. An interesting open question is whether activation of mbPR can result in gene regulation in the absence of ligand binding to intracellular progesterone receptor (iPR). This matter has been investigated in the past using P4 attached to serum albumin, but the attachment is leaky and albumin can be endocytosed and degraded, liberating P4. Here, we propose a more stringent approach to address this issue by ensuring attachment of P4 to the cell membrane via covalent binding to a stable phospholipid. This strategy identifies the actions of P4 independent from hormone binding to iPR. We found that a membrane-attached progestin can activate mbPR, the ERK signaling pathway leading to iPR phosphorylation, initial gene regulation and entry into the cell cycle, in the absence of detectable intracellular progestin.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/60809
http://dx.doi.org/10.1007/s00018-024-05116-3
url http://hdl.handle.net/10230/60809
http://dx.doi.org/10.1007/s00018-024-05116-3
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Cell Mol Life Sci. 2024 Feb 22;81(1):98
info:eu-repo/grantAgreement/EC/FP7/609989
info:eu-repo/grantAgreement/ES/2PE/PGC2018-099857-B-I00
info:eu-repo/grantAgreement/EC/H2020/825176
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Springer
publisher.none.fl_str_mv Springer
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869417429331869696
spelling A progesterone derivative linked to a stable phospholipid activates breast cancer cell response without leaving the cell membraneFont Mateu, Jofre, 1977-Sanllehí, PolSot, JesúsAbad, BeatrizMateos, NicolasTorreno-Pina, Juan A.Ferrari, RobertoWright, Roni H.G.Garcia-Parajo, Maria F.Joglar Tamargo, JesúsGoñi, Félix M.Beato, MiguelBreast cancer cellsCell membrane phospholipidsNuclear hormone receptorsProgesterone receptorProgesterone signalingIn hormone-responsive breast cancer cells, progesterone (P4) has been shown to act via its nuclear receptor (nPR), a ligand-activated transcription factor. A small fraction of progesterone receptor is palmitoylated and anchored to the cell membrane (mbPR) forming a complex with estrogen receptor alpha (ERα). Upon hormone exposure, either directly or via interaction with ERα, mbPR activates the SRC/RAS/ERK kinase pathway leading to phosphorylation of nPR by ERK. Kinase activation is essential for P4 gene regulation, as the ERK and MSK1 kinases are recruited by the nPR to its genomic binding sites and trigger chromatin remodeling. An interesting open question is whether activation of mbPR can result in gene regulation in the absence of ligand binding to intracellular progesterone receptor (iPR). This matter has been investigated in the past using P4 attached to serum albumin, but the attachment is leaky and albumin can be endocytosed and degraded, liberating P4. Here, we propose a more stringent approach to address this issue by ensuring attachment of P4 to the cell membrane via covalent binding to a stable phospholipid. This strategy identifies the actions of P4 independent from hormone binding to iPR. We found that a membrane-attached progestin can activate mbPR, the ERK signaling pathway leading to iPR phosphorylation, initial gene regulation and entry into the cell cycle, in the absence of detectable intracellular progestin.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was supported in part by the Spanish Ministerio de Ciencia e Innovación (MCI), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) (grant No. PGC2018-099857-B-I00), by the Basque Government (grants No. IT1625-22 and IT1270-19), by Fundación Ramón Areces (CIVP20A6619), by Fundación Biofísica Bizkaia, and by the Basque Excellence Research Centre (BERC) program of the Basque Government. This research was also supported by European Research Council (Project "4D Genome" 609989), the Ministerio de Economía y Competitividad (Project G62426937) and the Generalitat de Catalunya (Project AGAUR SGR 575 and AGAUR 2019PROD00115/IU68-016733), European Research Council -Proof Of Concept (Project “Impacct” 825176). This work has benefited from the equipment and framework of the COMP-HUB and COMP-R Initiatives, funded by the 'Departments of Excellence' Program of the Italian Ministry for University and Research (MIUR, 2018–2022 and MUR, 2022–2027).Springer202420242024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/60809http://dx.doi.org/10.1007/s00018-024-05116-3reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésCell Mol Life Sci. 2024 Feb 22;81(1):98info:eu-repo/grantAgreement/EC/FP7/609989info:eu-repo/grantAgreement/ES/2PE/PGC2018-099857-B-I00info:eu-repo/grantAgreement/EC/H2020/825176© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/608092026-05-29T05:05:01Z
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