p38ß (MAPK11) mediates gemcitabine-associated radiosensitivity in sarcoma experimental models

[Background and purpose]: Gemcitabine is an antitumour agent currently used in the treatment of several types of cancer with known properties as a radiosensitizer. p38MAPK signalling pathway has been shown to be a major determinant in the cellular response to gemcitabine in different experimental mo...

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Authors: Pascual-Serra, Raquel, Fernández-Aroca, Diego M., Sabater, Sebastiá, Roche, Olga, Andrés, I., Ortega-Muelas, Marta, Arconada-Luque, Elena, García-Flores, Natalia, Bossi, G., Belandia, Borja, Ruiz-Hidalgo, María J., Sánchez-Prieto, Ricardo
Format: article
Status:Versión aceptada para publicación
Publication Date:2021
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/242101
Online Access:http://hdl.handle.net/10261/242101
Access Level:Open access
Keyword:Gemcitabine, p38MAPK
MAPK11 (p38β)
MAPK14 (p38α)
Radiosensitivity
Sarcoma
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spelling p38ß (MAPK11) mediates gemcitabine-associated radiosensitivity in sarcoma experimental modelsPascual-Serra, RaquelFernández-Aroca, Diego M.Sabater, SebastiáRoche, OlgaAndrés, I.Ortega-Muelas, MartaArconada-Luque, ElenaGarcía-Flores, NataliaBossi, G.Belandia, BorjaRuiz-Hidalgo, María J.Sánchez-Prieto, RicardoGemcitabine, p38MAPKMAPK11 (p38β)MAPK14 (p38α)RadiosensitivitySarcoma[Background and purpose]: Gemcitabine is an antitumour agent currently used in the treatment of several types of cancer with known properties as a radiosensitizer. p38MAPK signalling pathway has been shown to be a major determinant in the cellular response to gemcitabine in different experimental models. However, the molecular mechanism implicated in gemcitabine-associated radiosensitivity remains unknown.[Materials and methods]: The human sarcoma cell lines A673 and HT1080, and a mouse cell line derived from a 3-methylcholanthrene induced sarcoma were used as experimental models. Modulation of p38MAPKs was performed by pharmacological approaches (SB203580) and genetic interference using lentiviral vectors coding for specific shRNAs. Viability was assessed by MTT. Gene expression was evaluated by western blot and RT-qPCR. Induction of apoptosis was monitored by caspase 3/7 activity. Response to ionizing radiation was evaluated by clonogenic assays.[Results]: Our data demonstrate that chemical inhibition of p38MAPK signalling pathway blocks gemcitabine radiosensitizing potential. Genetic interference of MAPK14 (p38¿), the most abundantly expressed and best characterized p38MAPK, despite promoting resistance to gemcitabine, it does not affect its radiosensitizing potential. Interestingly, specific knockdown of MAPK11 (p38ß) induces a total loss of the radiosensitivity associated to gemcitabine, as well as a marked increase in the resistance to the drug.[Conclusion]: The present work identifies p38ß as a major determinant of the radiosensitizing potential of gemcitabine without implication of p38¿, suggesting that p38ß status should be analysed in those cases in which gemcitabine is combined with ionizing radiation.This work was supported by grants from Fundación Leticia Castillejo Castillo, Ministerio de Ciencia, Innovación y Universidades (MCIU), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) (RTI2018-094093-B-I00) to RSP and MJRH. OR holds a contract for accessing the Spanish System of Science, Technology and Innovation (SECTI) funded by the University of Castilla-La Mancha (UCLM) and received partial support from the European Social Fund (FSE) through its Operative Program for Castilla-La Mancha (2007–2013). RSP and MJRH’s Research Institute, and the work carried out in their laboratory, received partial support from the European Community through the FEDER. RSP is a researcher of CSIC temporarily adscribed to UCLM.Peer reviewedElsevierFundación Leticia CastillejoMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)European CommissionUniversidad de Castilla La ManchaConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2021202120212021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttp://hdl.handle.net/10261/242101reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésInglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-094093-B-I00RTI2018-094093-B-I00/AEI/10.13039/501100011033http://dx.doi.org/10.1016/j.radonc.2020.12.008Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2421012026-05-22T06:33:51Z
dc.title.none.fl_str_mv p38ß (MAPK11) mediates gemcitabine-associated radiosensitivity in sarcoma experimental models
title p38ß (MAPK11) mediates gemcitabine-associated radiosensitivity in sarcoma experimental models
spellingShingle p38ß (MAPK11) mediates gemcitabine-associated radiosensitivity in sarcoma experimental models
Pascual-Serra, Raquel
Gemcitabine, p38MAPK
MAPK11 (p38β)
MAPK14 (p38α)
Radiosensitivity
Sarcoma
title_short p38ß (MAPK11) mediates gemcitabine-associated radiosensitivity in sarcoma experimental models
title_full p38ß (MAPK11) mediates gemcitabine-associated radiosensitivity in sarcoma experimental models
title_fullStr p38ß (MAPK11) mediates gemcitabine-associated radiosensitivity in sarcoma experimental models
title_full_unstemmed p38ß (MAPK11) mediates gemcitabine-associated radiosensitivity in sarcoma experimental models
title_sort p38ß (MAPK11) mediates gemcitabine-associated radiosensitivity in sarcoma experimental models
dc.creator.none.fl_str_mv Pascual-Serra, Raquel
Fernández-Aroca, Diego M.
Sabater, Sebastiá
Roche, Olga
Andrés, I.
Ortega-Muelas, Marta
Arconada-Luque, Elena
García-Flores, Natalia
Bossi, G.
Belandia, Borja
Ruiz-Hidalgo, María J.
Sánchez-Prieto, Ricardo
author Pascual-Serra, Raquel
author_facet Pascual-Serra, Raquel
Fernández-Aroca, Diego M.
Sabater, Sebastiá
Roche, Olga
Andrés, I.
Ortega-Muelas, Marta
Arconada-Luque, Elena
García-Flores, Natalia
Bossi, G.
Belandia, Borja
Ruiz-Hidalgo, María J.
Sánchez-Prieto, Ricardo
author_role author
author2 Fernández-Aroca, Diego M.
Sabater, Sebastiá
Roche, Olga
Andrés, I.
Ortega-Muelas, Marta
Arconada-Luque, Elena
García-Flores, Natalia
Bossi, G.
Belandia, Borja
Ruiz-Hidalgo, María J.
Sánchez-Prieto, Ricardo
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Fundación Leticia Castillejo
Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
European Commission
Universidad de Castilla La Mancha
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Gemcitabine, p38MAPK
MAPK11 (p38β)
MAPK14 (p38α)
Radiosensitivity
Sarcoma
topic Gemcitabine, p38MAPK
MAPK11 (p38β)
MAPK14 (p38α)
Radiosensitivity
Sarcoma
description [Background and purpose]: Gemcitabine is an antitumour agent currently used in the treatment of several types of cancer with known properties as a radiosensitizer. p38MAPK signalling pathway has been shown to be a major determinant in the cellular response to gemcitabine in different experimental models. However, the molecular mechanism implicated in gemcitabine-associated radiosensitivity remains unknown.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Postprint
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/242101
url http://hdl.handle.net/10261/242101
dc.language.none.fl_str_mv Inglés
Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-094093-B-I00
RTI2018-094093-B-I00/AEI/10.13039/501100011033
http://dx.doi.org/10.1016/j.radonc.2020.12.008
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
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
repository.mail.fl_str_mv
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score 15,812429

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