Knockdown of α2,3-Sialyltransferases Impairs Pancreatic Cancer Cell Migration, Invasion and E-selectin-Dependent Adhesion
Aberrant sialylation is frequently found in pancreatic ductal adenocarcinoma (PDA). α2,3-Sialyltransferases (α2,3-STs) ST3GAL3 and ST3GAL4 are overexpressed in PDA tissues and are responsible for increased biosynthesis of sialyl-Lewis (sLe) antigens, which play an important role in metastasis. This...
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MDPI AG
2020-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/17/6239 |
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| author | Pedro Enrique Guerrero Laura Miró Bin S. Wong Anna Massaguer Neus Martínez-Bosch Rafael de Llorens Pilar Navarro Konstantinos Konstantopoulos Esther Llop Rosa Peracaula |
| author_facet | Pedro Enrique Guerrero Laura Miró Bin S. Wong Anna Massaguer Neus Martínez-Bosch Rafael de Llorens Pilar Navarro Konstantinos Konstantopoulos Esther Llop Rosa Peracaula |
| author_sort | Pedro Enrique Guerrero |
| collection | DOAJ |
| description | Aberrant sialylation is frequently found in pancreatic ductal adenocarcinoma (PDA). α2,3-Sialyltransferases (α2,3-STs) ST3GAL3 and ST3GAL4 are overexpressed in PDA tissues and are responsible for increased biosynthesis of sialyl-Lewis (sLe) antigens, which play an important role in metastasis. This study addresses the effect of α2,3-STs knockdown on the migratory and invasive phenotype of PDA cells, and on E-selectin-dependent adhesion. Characterization of the cell sialome, the α2,3-STs and fucosyltransferases involved in the biosynthesis of sLe antigens, using a panel of human PDA cells showed differences in the levels of sialylated determinants and α2,3-STs expression, reflecting their phenotypic heterogeneity. Knockdown of ST3GAL3 and ST3GAL4 in BxPC-3 and Capan-1 cells, which expressed moderate to high levels of sLe antigens and α2,3-STs, led to a significant reduction in sLe<sup>x</sup> and in most cases in sLe<sup>a</sup>, with slight increases in the α2,6-sialic acid content. Moreover, ST3GAL3 and ST3GAL4 downregulation resulted in a significant decrease in cell migration and invasion. Binding and rolling to E-selectin, which represent key steps in metastasis, were also markedly impaired in the α2,3-STs knockdown cells. Our results indicate that inhibition of ST3GAL3 and ST3GAL4 may be a novel strategy to block PDA metastasis, which is one of the reasons for its dismal prognosis. |
| first_indexed | 2024-03-10T16:44:10Z |
| format | Article |
| id | doaj.art-b64ba1990cbc4045afab291f9f102d67 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T16:44:10Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b64ba1990cbc4045afab291f9f102d672023-11-20T11:45:45ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-08-012117623910.3390/ijms21176239Knockdown of α2,3-Sialyltransferases Impairs Pancreatic Cancer Cell Migration, Invasion and E-selectin-Dependent AdhesionPedro Enrique Guerrero0Laura Miró1Bin S. Wong2Anna Massaguer3Neus Martínez-Bosch4Rafael de Llorens5Pilar Navarro6Konstantinos Konstantopoulos7Esther Llop8Rosa Peracaula9Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, 17003 Girona, SpainDepartment of Biology, Biochemistry and Molecular Biology Unit, University of Girona, 17003 Girona, SpainDepartment of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USADepartment of Biology, Biochemistry and Molecular Biology Unit, University of Girona, 17003 Girona, SpainCancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada IIBB-CSIC, 08003 Barcelona, SpainDepartment of Biology, Biochemistry and Molecular Biology Unit, University of Girona, 17003 Girona, SpainCancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada IIBB-CSIC, 08003 Barcelona, SpainDepartment of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USADepartment of Biology, Biochemistry and Molecular Biology Unit, University of Girona, 17003 Girona, SpainDepartment of Biology, Biochemistry and Molecular Biology Unit, University of Girona, 17003 Girona, SpainAberrant sialylation is frequently found in pancreatic ductal adenocarcinoma (PDA). α2,3-Sialyltransferases (α2,3-STs) ST3GAL3 and ST3GAL4 are overexpressed in PDA tissues and are responsible for increased biosynthesis of sialyl-Lewis (sLe) antigens, which play an important role in metastasis. This study addresses the effect of α2,3-STs knockdown on the migratory and invasive phenotype of PDA cells, and on E-selectin-dependent adhesion. Characterization of the cell sialome, the α2,3-STs and fucosyltransferases involved in the biosynthesis of sLe antigens, using a panel of human PDA cells showed differences in the levels of sialylated determinants and α2,3-STs expression, reflecting their phenotypic heterogeneity. Knockdown of ST3GAL3 and ST3GAL4 in BxPC-3 and Capan-1 cells, which expressed moderate to high levels of sLe antigens and α2,3-STs, led to a significant reduction in sLe<sup>x</sup> and in most cases in sLe<sup>a</sup>, with slight increases in the α2,6-sialic acid content. Moreover, ST3GAL3 and ST3GAL4 downregulation resulted in a significant decrease in cell migration and invasion. Binding and rolling to E-selectin, which represent key steps in metastasis, were also markedly impaired in the α2,3-STs knockdown cells. Our results indicate that inhibition of ST3GAL3 and ST3GAL4 may be a novel strategy to block PDA metastasis, which is one of the reasons for its dismal prognosis.https://www.mdpi.com/1422-0067/21/17/6239pancreatic ductal adenocarcinomaα2,3-sialyltransferasessialyl-Lewis antigensE-selectincell migration |
| spellingShingle | Pedro Enrique Guerrero Laura Miró Bin S. Wong Anna Massaguer Neus Martínez-Bosch Rafael de Llorens Pilar Navarro Konstantinos Konstantopoulos Esther Llop Rosa Peracaula Knockdown of α2,3-Sialyltransferases Impairs Pancreatic Cancer Cell Migration, Invasion and E-selectin-Dependent Adhesion International Journal of Molecular Sciences pancreatic ductal adenocarcinoma α2,3-sialyltransferases sialyl-Lewis antigens E-selectin cell migration |
| title | Knockdown of α2,3-Sialyltransferases Impairs Pancreatic Cancer Cell Migration, Invasion and E-selectin-Dependent Adhesion |
| title_full | Knockdown of α2,3-Sialyltransferases Impairs Pancreatic Cancer Cell Migration, Invasion and E-selectin-Dependent Adhesion |
| title_fullStr | Knockdown of α2,3-Sialyltransferases Impairs Pancreatic Cancer Cell Migration, Invasion and E-selectin-Dependent Adhesion |
| title_full_unstemmed | Knockdown of α2,3-Sialyltransferases Impairs Pancreatic Cancer Cell Migration, Invasion and E-selectin-Dependent Adhesion |
| title_short | Knockdown of α2,3-Sialyltransferases Impairs Pancreatic Cancer Cell Migration, Invasion and E-selectin-Dependent Adhesion |
| title_sort | knockdown of α2 3 sialyltransferases impairs pancreatic cancer cell migration invasion and e selectin dependent adhesion |
| topic | pancreatic ductal adenocarcinoma α2,3-sialyltransferases sialyl-Lewis antigens E-selectin cell migration |
| url | https://www.mdpi.com/1422-0067/21/17/6239 |
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