The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cells
Autor(a) principal: | |
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Data de Publicação: | 2007 |
Outros Autores: | , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/1822/67811 |
Resumo: | Gefitinib is a specific inhibitor of the epidermal growth factor receptor (EGFR) that causes growth delay in cancer cell lines and human tumor xenografts expressing high levels of EGFR. An understanding of the downstream cellular targets of gefitinib will allow the discovery of biomarkers for predicting outcomes and monitoring anti-EGFR therapies and provide information for key targets for therapeutic intervention. In this study, we investigated the role of FOXO3a in gefitinib action and resistance. Using two gefitinib-sensitive (i.e., BT474 and SKBR3) as well as three other resistant breast carcinoma cell lines (i.e., MCF-7, MDA-MB-231, and MDA-MB-453), we showed that gefitinib targets the transcription factor FOXO3a to mediate cell cycle arrest and cell death in sensitive breast cancer cells. In the sensitive cells, gefitinib treatment causes cell cycle arrest predominantly at the G(0)-G(1) phase and apoptosis, which is associated with FOXO3a dephosphorylation at Akt sites and nuclear translocation, whereas in the resistant cells, FOXO3a stays phosphorylated and remains in the cytoplasm. The nuclear accumulation of FOXO3a in response to gefitinib was confirmed in tumor tissue sections from breast cancer patients presurgically treated with gefitinib as monotherapy. We also showed that knockdown of FOXO3a expression using small interfering RNA (siRNA) can rescue sensitive BT474 cells from gefitinib-induced cell-proliferative arrest, whereas reintroduction of active FOXO3a in resistant MDA-MB-231 cells can at least partially restore cell-proliferative arrest and sensitivity to gefitinib. These results suggest that the FOXO3a dephosphorylation and nuclear localization have a direct role in mediating the gefitinib-induced proliferative arrest and in determining sensitivity to gefitinib. |
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The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cellsAntineoplastic agentsBlotting, WesternBreast neoplasmsCell line, TumorCell proliferationErbB receptorsForkhead box protein O3Forkhead transcription factorsG1 phaseGefitinibGene silencingHumansImmunohistochemistryQuinazolinesRNA, Small interferingResting phase, Cell cycleScience & TechnologyGefitinib is a specific inhibitor of the epidermal growth factor receptor (EGFR) that causes growth delay in cancer cell lines and human tumor xenografts expressing high levels of EGFR. An understanding of the downstream cellular targets of gefitinib will allow the discovery of biomarkers for predicting outcomes and monitoring anti-EGFR therapies and provide information for key targets for therapeutic intervention. In this study, we investigated the role of FOXO3a in gefitinib action and resistance. Using two gefitinib-sensitive (i.e., BT474 and SKBR3) as well as three other resistant breast carcinoma cell lines (i.e., MCF-7, MDA-MB-231, and MDA-MB-453), we showed that gefitinib targets the transcription factor FOXO3a to mediate cell cycle arrest and cell death in sensitive breast cancer cells. In the sensitive cells, gefitinib treatment causes cell cycle arrest predominantly at the G(0)-G(1) phase and apoptosis, which is associated with FOXO3a dephosphorylation at Akt sites and nuclear translocation, whereas in the resistant cells, FOXO3a stays phosphorylated and remains in the cytoplasm. The nuclear accumulation of FOXO3a in response to gefitinib was confirmed in tumor tissue sections from breast cancer patients presurgically treated with gefitinib as monotherapy. We also showed that knockdown of FOXO3a expression using small interfering RNA (siRNA) can rescue sensitive BT474 cells from gefitinib-induced cell-proliferative arrest, whereas reintroduction of active FOXO3a in resistant MDA-MB-231 cells can at least partially restore cell-proliferative arrest and sensitivity to gefitinib. These results suggest that the FOXO3a dephosphorylation and nuclear localization have a direct role in mediating the gefitinib-induced proliferative arrest and in determining sensitivity to gefitinib.Supported by the German Cancer Aide Foundation (J. Krol)and the Association of International Cancer Research (R. Francis).Andrew Sunters and Andreas Polychronic were fellows funded by CancerResearch UK. Andre Albergaria is a recipient of a grant from Fundação para a Ciência e a Tecnologia, Portugal. This work was sponsored by theBreast Cancer Research Trust and Cancer Research UKAmerican Association for Cancer ResearchUniversidade do MinhoKrol, JannaFrancis, Richard E.Albergaria, AndréSunters, AndrewPolychronis, AndreasCoombes, R. CharlesLam, Eric W.-F.2007-122007-12-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/1822/67811eng1535-71631538-851410.1158/1535-7163.MCT-07-050718089711https://mct.aacrjournals.org/content/6/12/3169info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-21T12:04:44Zoai:repositorium.sdum.uminho.pt:1822/67811Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:55:03.128470Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cells |
title |
The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cells |
spellingShingle |
The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cells Krol, Janna Antineoplastic agents Blotting, Western Breast neoplasms Cell line, Tumor Cell proliferation ErbB receptors Forkhead box protein O3 Forkhead transcription factors G1 phase Gefitinib Gene silencing Humans Immunohistochemistry Quinazolines RNA, Small interfering Resting phase, Cell cycle Science & Technology |
title_short |
The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cells |
title_full |
The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cells |
title_fullStr |
The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cells |
title_full_unstemmed |
The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cells |
title_sort |
The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cells |
author |
Krol, Janna |
author_facet |
Krol, Janna Francis, Richard E. Albergaria, André Sunters, Andrew Polychronis, Andreas Coombes, R. Charles Lam, Eric W.-F. |
author_role |
author |
author2 |
Francis, Richard E. Albergaria, André Sunters, Andrew Polychronis, Andreas Coombes, R. Charles Lam, Eric W.-F. |
author2_role |
author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Krol, Janna Francis, Richard E. Albergaria, André Sunters, Andrew Polychronis, Andreas Coombes, R. Charles Lam, Eric W.-F. |
dc.subject.por.fl_str_mv |
Antineoplastic agents Blotting, Western Breast neoplasms Cell line, Tumor Cell proliferation ErbB receptors Forkhead box protein O3 Forkhead transcription factors G1 phase Gefitinib Gene silencing Humans Immunohistochemistry Quinazolines RNA, Small interfering Resting phase, Cell cycle Science & Technology |
topic |
Antineoplastic agents Blotting, Western Breast neoplasms Cell line, Tumor Cell proliferation ErbB receptors Forkhead box protein O3 Forkhead transcription factors G1 phase Gefitinib Gene silencing Humans Immunohistochemistry Quinazolines RNA, Small interfering Resting phase, Cell cycle Science & Technology |
description |
Gefitinib is a specific inhibitor of the epidermal growth factor receptor (EGFR) that causes growth delay in cancer cell lines and human tumor xenografts expressing high levels of EGFR. An understanding of the downstream cellular targets of gefitinib will allow the discovery of biomarkers for predicting outcomes and monitoring anti-EGFR therapies and provide information for key targets for therapeutic intervention. In this study, we investigated the role of FOXO3a in gefitinib action and resistance. Using two gefitinib-sensitive (i.e., BT474 and SKBR3) as well as three other resistant breast carcinoma cell lines (i.e., MCF-7, MDA-MB-231, and MDA-MB-453), we showed that gefitinib targets the transcription factor FOXO3a to mediate cell cycle arrest and cell death in sensitive breast cancer cells. In the sensitive cells, gefitinib treatment causes cell cycle arrest predominantly at the G(0)-G(1) phase and apoptosis, which is associated with FOXO3a dephosphorylation at Akt sites and nuclear translocation, whereas in the resistant cells, FOXO3a stays phosphorylated and remains in the cytoplasm. The nuclear accumulation of FOXO3a in response to gefitinib was confirmed in tumor tissue sections from breast cancer patients presurgically treated with gefitinib as monotherapy. We also showed that knockdown of FOXO3a expression using small interfering RNA (siRNA) can rescue sensitive BT474 cells from gefitinib-induced cell-proliferative arrest, whereas reintroduction of active FOXO3a in resistant MDA-MB-231 cells can at least partially restore cell-proliferative arrest and sensitivity to gefitinib. These results suggest that the FOXO3a dephosphorylation and nuclear localization have a direct role in mediating the gefitinib-induced proliferative arrest and in determining sensitivity to gefitinib. |
publishDate |
2007 |
dc.date.none.fl_str_mv |
2007-12 2007-12-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/1822/67811 |
url |
http://hdl.handle.net/1822/67811 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
1535-7163 1538-8514 10.1158/1535-7163.MCT-07-0507 18089711 https://mct.aacrjournals.org/content/6/12/3169 |
dc.rights.driver.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 |
American Association for Cancer Research |
publisher.none.fl_str_mv |
American Association for Cancer Research |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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