ERK5 signalling pathway is a novel target of sorafenib: Implication in EGF biology
Sorafenib is a multikinase inhibitor widely used in cancer therapy with an antitumoureffect related to biological processes as proliferation, migration or invasion, amongothers. Initially designed as a Raf inhibitor, Sorafenib was later shown to also block keymolecules in tumour progression such as...
| Authors: | ; ; ; ; ; ; ; ; ; ; ; |
|---|---|
| Format: | Article |
| Publication date: | 2021 |
| Country: | España |
| Institution: | Universidad Autónoma de Madrid |
| Repository: | Biblos-e Archivo. Repositorio Institucional de la UAM |
| Language: | English |
| OAI Identifier: | oai:dnet:biblosearchi::01db6932f8d37be696bd1c03e94dcf16 |
| Online Access: | https://hdl.handle.net/10486/773000 https://dx.doi.org/10.1111/jcmm.16990 |
| Access Level: | Open access |
| Keyword: | EGF ERK5 MEK5 Sorafenib Biología y Biomedicina / Biología Química Medicina |
| _version_ | 1878741152079806464 |
|---|---|
| author | Ortega Muelas, Marta |
| author2 | Roche, Olga Fernández-Aroca, Diego M. Encinar, José Antonio Albandea Rodríguez, David Arconada-Luque, Elena Pascual-Serra, Raquel Muñoz, Ismael Sánchez Pérez, María Isabel Belandia Gómez, Borja Ruiz-Hidalgo, María José Sánchez-Prieto, Ricardo |
| author2_role | author author author author author author author author author author author |
| author_browse | Albandea Rodríguez, David Arconada-Luque, Elena Belandia Gómez, Borja Encinar, José Antonio Fernández-Aroca, Diego M. Muñoz, Ismael Ortega Muelas, Marta Pascual-Serra, Raquel Roche, Olga Ruiz-Hidalgo, María José Sánchez Pérez, María Isabel Sánchez-Prieto, Ricardo |
| author_facet | Ortega Muelas, Marta Roche, Olga Fernández-Aroca, Diego M. Encinar, José Antonio Albandea Rodríguez, David Arconada-Luque, Elena Pascual-Serra, Raquel Muñoz, Ismael Sánchez Pérez, María Isabel Belandia Gómez, Borja Ruiz-Hidalgo, María José Sánchez-Prieto, Ricardo |
| author_role | author |
| collection | Biblos-e Archivo. Repositorio Institucional de la UAM |
| description | Sorafenib is a multikinase inhibitor widely used in cancer therapy with an antitumoureffect related to biological processes as proliferation, migration or invasion, amongothers. Initially designed as a Raf inhibitor, Sorafenib was later shown to also block keymolecules in tumour progression such as VEGFR and PDGFR. In addition, sorafenibhas been connected with key signalling pathways in cancer such as EGFR/EGF.However, no definitive clue about the molecular mechanism linking sorafenib andEGF signalling pathway has been established so far. Our data in HeLa, U2OS, A549and HEK293T cells, based on in silico, chemical and genetic approaches demonstratethat the MEK5/ERK5 signalling pathway is a novel target of sorafenib. In addition, ourdata show how sorafenib is able to block MEK5- dependent phosphorylation of ERK5in the Ser218/Tyr220, affecting the transcriptional activation associated with ERK5.Moreover, we demonstrate that some of the effects of this kinase inhibitor onto EGFbiological responses, such as progression through cell cycle or migration, are mediatedthrough the effect exerted onto ERK5 signalling pathway. Therefore, our observations describe a novel target of sorafenib, the ERK5 signalling pathway, and establish newmechanistic insights for the antitumour effect of this multikinase inhibitor |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_e00a86e957e8324f4cd5e7a125b1fcaf |
| identifier_str_mv | 34655447 |
| institution | Universidad Autónoma de Madrid |
| instname_str | Universidad Autónoma de Madrid |
| language | eng |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:dnet:biblosearchi::01db6932f8d37be696bd1c03e94dcf16 |
| publishDate | 2021 |
| publishDateSort | 2021 |
| publisher | Wiley |
| publisherStr | Wiley |
| reponame_str | Biblos-e Archivo. Repositorio Institucional de la UAM |
| spelling | ERK5 signalling pathway is a novel target of sorafenib: Implication in EGF biology Ortega Muelas, Marta Roche, Olga Fernández-Aroca, Diego M. Encinar, José Antonio Albandea Rodríguez, David Arconada-Luque, Elena Pascual-Serra, Raquel Muñoz, Ismael Sánchez Pérez, María Isabel Belandia Gómez, Borja Ruiz-Hidalgo, María José Sánchez-Prieto, Ricardo EGF ERK5 MEK5 Sorafenib Biología y Biomedicina / Biología Química Medicina Sorafenib is a multikinase inhibitor widely used in cancer therapy with an antitumoureffect related to biological processes as proliferation, migration or invasion, amongothers. Initially designed as a Raf inhibitor, Sorafenib was later shown to also block keymolecules in tumour progression such as VEGFR and PDGFR. In addition, sorafenibhas been connected with key signalling pathways in cancer such as EGFR/EGF.However, no definitive clue about the molecular mechanism linking sorafenib andEGF signalling pathway has been established so far. Our data in HeLa, U2OS, A549and HEK293T cells, based on in silico, chemical and genetic approaches demonstratethat the MEK5/ERK5 signalling pathway is a novel target of sorafenib. In addition, ourdata show how sorafenib is able to block MEK5- dependent phosphorylation of ERK5in the Ser218/Tyr220, affecting the transcriptional activation associated with ERK5.Moreover, we demonstrate that some of the effects of this kinase inhibitor onto EGFbiological responses, such as progression through cell cycle or migration, are mediatedthrough the effect exerted onto ERK5 signalling pathway. Therefore, our observations describe a novel target of sorafenib, the ERK5 signalling pathway, and establish newmechanistic insights for the antitumour effect of this multikinase inhibitor 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 Europeode Desarrollo Regional (FEDER) (RTI2018- 094093-B-I00) toRSP and MJRH. OR holds a contract for accessing the Spanish System of Science, Technology, and Innovation (SECTI) fundedby 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. RPS and EAL hold a research predoctoralcontract cofounded by the European Social Fund and UCLM. The Spanish Ministry of Economy and Competitiveness (MINECO,Project RTI2018- 096724-B- C21) and the Generalitat Valenciana (PROMETEO/2016/006) support work in the Encinar´s laboratory. Authors are grateful to Dr.G- Ferrer Mayorga for her assistance in the transwell assays, and to the ‘Centro de Computación Científica’ (CCC-UAM) for letting us to take advantage of the com-puter cluster Cibeles (https://www.ccc.uam.es/) and for providing computing facilities Wiley https://hdl.handle.net/10486/773000 https://dx.doi.org/10.1111/jcmm.16990 34655447 |
| spellingShingle | ERK5 signalling pathway is a novel target of sorafenib: Implication in EGF biology Ortega Muelas, Marta EGF ERK5 MEK5 Sorafenib Biología y Biomedicina / Biología Química Medicina |
| title | ERK5 signalling pathway is a novel target of sorafenib: Implication in EGF biology |
| title_full | ERK5 signalling pathway is a novel target of sorafenib: Implication in EGF biology |
| title_fullStr | ERK5 signalling pathway is a novel target of sorafenib: Implication in EGF biology |
| title_full_unstemmed | ERK5 signalling pathway is a novel target of sorafenib: Implication in EGF biology |
| title_short | ERK5 signalling pathway is a novel target of sorafenib: Implication in EGF biology |
| title_sort | ERK5 signalling pathway is a novel target of sorafenib: Implication in EGF biology |
| topic | EGF ERK5 MEK5 Sorafenib Biología y Biomedicina / Biología Química Medicina |
| topic_facet | EGF ERK5 MEK5 Sorafenib Biología y Biomedicina / Biología Química Medicina |
| url | https://hdl.handle.net/10486/773000 https://dx.doi.org/10.1111/jcmm.16990 |