Inhibition of Fucosylation in Human Invasive Ductal Carcinoma Reduces E-Selectin Ligand Expression, Cell Proliferation, and ERK1/2 and p38 MAPK Activation
Autor(a) principal: | |
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Data de Publicação: | 2018 |
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/10400.17/3949 |
Resumo: | Breast cancer tissue overexpresses fucosylated glycans, such as sialyl-Lewis X/A (sLeX/A ), and α-1,3/4-fucosyltransferases (FUTs) in relation to increased disease progression and metastasis. These glycans in tumor circulating cells mediate binding to vascular E-selectin, initiating tumor extravasation. However, their role in breast carcinogenesis is still unknown. Here, we aimed to define the contribution of the fucosylated structures, including sLeX/A , to cell adhesion, cell signaling, and cell proliferation in invasive ductal carcinomas (IDC), the most frequent type of breast cancer. We first analyzed expression of E-selectin ligands in IDC tissue and established primary cell cultures from the tissue. We observed strong reactivity with E-selectin and anti-sLeX/A antibodies in both IDC tissue and cell lines, and expression of α-1,3/4 FUTs FUT4, FUT5, FUT6, FUT10, and FUT11. To further assess the role of fucosylation in IDC biology, we immortalized a primary IDC cell line with human telomerase reverse transcriptase to create the 'CF1_T cell line'. Treatment with 2-fluorofucose (2-FF), a fucosylation inhibitor, completely abrogated its sLeX/A expression and dramatically reduced adherence of CF1_T cells to E-selectin under hemodynamic flow conditions. In addition, 2-FF-treated CF1_T cells showed a reduced migratory ability, as well as decreased cell proliferation rate. Notably, 2-FF treatment lowered the growth factor expression of CF1_T cells, prominently for FGF2, vascular endothelial growth factor, and transforming growth factor beta, and negatively affected activation of signal-regulating protein kinases 1 and 2 and p38 mitogen-activated protein kinase signaling pathways. These data indicate that fucosylation licenses several malignant features of IDC, such as cell adhesion, migration, proliferation, and growth factor expression, contributing to tumor progression. |
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Inhibition of Fucosylation in Human Invasive Ductal Carcinoma Reduces E-Selectin Ligand Expression, Cell Proliferation, and ERK1/2 and p38 MAPK ActivationHSJ ANPATAdultAgedFemaleHumansBreast Neoplasms / enzymology*Middle AgedBreast Neoplasms / pathologyCarcinoma, Ductal, Breast / enzymology*Carcinoma, Ductal, Breast / pathologyCell Adhesion / drug effectsCell Line, TumorCell Proliferation / drug effectsE-Selectin / geneticsE-Selectin / metabolism*Fucose / analogs & derivativesFucose / pharmacologyFucosyltransferases / antagonists & inhibitors*LigandsMAP Kinase Signaling System / drug effectsNeoplasm InvasivenessOligosaccharides / metabolism*Primary Cell CultureSialyl Lewis X Antigenp38 Mitogen-Activated Protein Kinases / geneticsp38 Mitogen-Activated Protein Kinases / metabolism*Breast cancer tissue overexpresses fucosylated glycans, such as sialyl-Lewis X/A (sLeX/A ), and α-1,3/4-fucosyltransferases (FUTs) in relation to increased disease progression and metastasis. These glycans in tumor circulating cells mediate binding to vascular E-selectin, initiating tumor extravasation. However, their role in breast carcinogenesis is still unknown. Here, we aimed to define the contribution of the fucosylated structures, including sLeX/A , to cell adhesion, cell signaling, and cell proliferation in invasive ductal carcinomas (IDC), the most frequent type of breast cancer. We first analyzed expression of E-selectin ligands in IDC tissue and established primary cell cultures from the tissue. We observed strong reactivity with E-selectin and anti-sLeX/A antibodies in both IDC tissue and cell lines, and expression of α-1,3/4 FUTs FUT4, FUT5, FUT6, FUT10, and FUT11. To further assess the role of fucosylation in IDC biology, we immortalized a primary IDC cell line with human telomerase reverse transcriptase to create the 'CF1_T cell line'. Treatment with 2-fluorofucose (2-FF), a fucosylation inhibitor, completely abrogated its sLeX/A expression and dramatically reduced adherence of CF1_T cells to E-selectin under hemodynamic flow conditions. In addition, 2-FF-treated CF1_T cells showed a reduced migratory ability, as well as decreased cell proliferation rate. Notably, 2-FF treatment lowered the growth factor expression of CF1_T cells, prominently for FGF2, vascular endothelial growth factor, and transforming growth factor beta, and negatively affected activation of signal-regulating protein kinases 1 and 2 and p38 mitogen-activated protein kinase signaling pathways. These data indicate that fucosylation licenses several malignant features of IDC, such as cell adhesion, migration, proliferation, and growth factor expression, contributing to tumor progression.WileyRepositório do Centro Hospitalar Universitário de Lisboa Central, EPECarrascal, MSilva, MRamalho, JPen, CMartins, MPascoal, CAmaral, CSerrano, IOliveira, MJSackstein, RVideira, P2022-01-04T11:28:45Z20182018-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.17/3949engMol Oncol. 2018 May;12(5):579-593.10.1002/1878-0261.12163.info: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:RCAAP2023-03-10T09:44:42ZPortal AgregadorONG |
dc.title.none.fl_str_mv |
Inhibition of Fucosylation in Human Invasive Ductal Carcinoma Reduces E-Selectin Ligand Expression, Cell Proliferation, and ERK1/2 and p38 MAPK Activation |
title |
Inhibition of Fucosylation in Human Invasive Ductal Carcinoma Reduces E-Selectin Ligand Expression, Cell Proliferation, and ERK1/2 and p38 MAPK Activation |
spellingShingle |
Inhibition of Fucosylation in Human Invasive Ductal Carcinoma Reduces E-Selectin Ligand Expression, Cell Proliferation, and ERK1/2 and p38 MAPK Activation Carrascal, M HSJ ANPAT Adult Aged Female Humans Breast Neoplasms / enzymology* Middle Aged Breast Neoplasms / pathology Carcinoma, Ductal, Breast / enzymology* Carcinoma, Ductal, Breast / pathology Cell Adhesion / drug effects Cell Line, Tumor Cell Proliferation / drug effects E-Selectin / genetics E-Selectin / metabolism* Fucose / analogs & derivatives Fucose / pharmacology Fucosyltransferases / antagonists & inhibitors* Ligands MAP Kinase Signaling System / drug effects Neoplasm Invasiveness Oligosaccharides / metabolism* Primary Cell Culture Sialyl Lewis X Antigen p38 Mitogen-Activated Protein Kinases / genetics p38 Mitogen-Activated Protein Kinases / metabolism* |
title_short |
Inhibition of Fucosylation in Human Invasive Ductal Carcinoma Reduces E-Selectin Ligand Expression, Cell Proliferation, and ERK1/2 and p38 MAPK Activation |
title_full |
Inhibition of Fucosylation in Human Invasive Ductal Carcinoma Reduces E-Selectin Ligand Expression, Cell Proliferation, and ERK1/2 and p38 MAPK Activation |
title_fullStr |
Inhibition of Fucosylation in Human Invasive Ductal Carcinoma Reduces E-Selectin Ligand Expression, Cell Proliferation, and ERK1/2 and p38 MAPK Activation |
title_full_unstemmed |
Inhibition of Fucosylation in Human Invasive Ductal Carcinoma Reduces E-Selectin Ligand Expression, Cell Proliferation, and ERK1/2 and p38 MAPK Activation |
title_sort |
Inhibition of Fucosylation in Human Invasive Ductal Carcinoma Reduces E-Selectin Ligand Expression, Cell Proliferation, and ERK1/2 and p38 MAPK Activation |
author |
Carrascal, M |
author_facet |
Carrascal, M Silva, M Ramalho, J Pen, C Martins, M Pascoal, C Amaral, C Serrano, I Oliveira, MJ Sackstein, R Videira, P |
author_role |
author |
author2 |
Silva, M Ramalho, J Pen, C Martins, M Pascoal, C Amaral, C Serrano, I Oliveira, MJ Sackstein, R Videira, P |
author2_role |
author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório do Centro Hospitalar Universitário de Lisboa Central, EPE |
dc.contributor.author.fl_str_mv |
Carrascal, M Silva, M Ramalho, J Pen, C Martins, M Pascoal, C Amaral, C Serrano, I Oliveira, MJ Sackstein, R Videira, P |
dc.subject.por.fl_str_mv |
HSJ ANPAT Adult Aged Female Humans Breast Neoplasms / enzymology* Middle Aged Breast Neoplasms / pathology Carcinoma, Ductal, Breast / enzymology* Carcinoma, Ductal, Breast / pathology Cell Adhesion / drug effects Cell Line, Tumor Cell Proliferation / drug effects E-Selectin / genetics E-Selectin / metabolism* Fucose / analogs & derivatives Fucose / pharmacology Fucosyltransferases / antagonists & inhibitors* Ligands MAP Kinase Signaling System / drug effects Neoplasm Invasiveness Oligosaccharides / metabolism* Primary Cell Culture Sialyl Lewis X Antigen p38 Mitogen-Activated Protein Kinases / genetics p38 Mitogen-Activated Protein Kinases / metabolism* |
topic |
HSJ ANPAT Adult Aged Female Humans Breast Neoplasms / enzymology* Middle Aged Breast Neoplasms / pathology Carcinoma, Ductal, Breast / enzymology* Carcinoma, Ductal, Breast / pathology Cell Adhesion / drug effects Cell Line, Tumor Cell Proliferation / drug effects E-Selectin / genetics E-Selectin / metabolism* Fucose / analogs & derivatives Fucose / pharmacology Fucosyltransferases / antagonists & inhibitors* Ligands MAP Kinase Signaling System / drug effects Neoplasm Invasiveness Oligosaccharides / metabolism* Primary Cell Culture Sialyl Lewis X Antigen p38 Mitogen-Activated Protein Kinases / genetics p38 Mitogen-Activated Protein Kinases / metabolism* |
description |
Breast cancer tissue overexpresses fucosylated glycans, such as sialyl-Lewis X/A (sLeX/A ), and α-1,3/4-fucosyltransferases (FUTs) in relation to increased disease progression and metastasis. These glycans in tumor circulating cells mediate binding to vascular E-selectin, initiating tumor extravasation. However, their role in breast carcinogenesis is still unknown. Here, we aimed to define the contribution of the fucosylated structures, including sLeX/A , to cell adhesion, cell signaling, and cell proliferation in invasive ductal carcinomas (IDC), the most frequent type of breast cancer. We first analyzed expression of E-selectin ligands in IDC tissue and established primary cell cultures from the tissue. We observed strong reactivity with E-selectin and anti-sLeX/A antibodies in both IDC tissue and cell lines, and expression of α-1,3/4 FUTs FUT4, FUT5, FUT6, FUT10, and FUT11. To further assess the role of fucosylation in IDC biology, we immortalized a primary IDC cell line with human telomerase reverse transcriptase to create the 'CF1_T cell line'. Treatment with 2-fluorofucose (2-FF), a fucosylation inhibitor, completely abrogated its sLeX/A expression and dramatically reduced adherence of CF1_T cells to E-selectin under hemodynamic flow conditions. In addition, 2-FF-treated CF1_T cells showed a reduced migratory ability, as well as decreased cell proliferation rate. Notably, 2-FF treatment lowered the growth factor expression of CF1_T cells, prominently for FGF2, vascular endothelial growth factor, and transforming growth factor beta, and negatively affected activation of signal-regulating protein kinases 1 and 2 and p38 mitogen-activated protein kinase signaling pathways. These data indicate that fucosylation licenses several malignant features of IDC, such as cell adhesion, migration, proliferation, and growth factor expression, contributing to tumor progression. |
publishDate |
2018 |
dc.date.none.fl_str_mv |
2018 2018-01-01T00:00:00Z 2022-01-04T11:28:45Z |
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/10400.17/3949 |
url |
http://hdl.handle.net/10400.17/3949 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Mol Oncol. 2018 May;12(5):579-593. 10.1002/1878-0261.12163. |
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 |
Wiley |
publisher.none.fl_str_mv |
Wiley |
dc.source.none.fl_str_mv |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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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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