TY - JOUR
T1 - Knockdown of α2,3-sialyltransferases impairs pancreatic cancer cell migration, invasion and e-selectin-dependent adhesion
AU - Guerrero, Pedro Enrique
AU - Miró, Laura
AU - Wong, Bin S.
AU - Massaguer, Anna
AU - Martínez-Bosch, Neus
AU - de Llorens, Rafael
AU - Navarro, Pilar
AU - Konstantopoulos, Konstantinos
AU - Llop, Esther
AU - Peracaula, Rosa
N1 - Funding Information:
Acknowledgments: P.E.G. acknowledges funding support from the University of Girona for mobility grant and from the Generalitat of Catalunya for a pre-doctoral fellowship F.I. L.M. also acknowledges funding from the Generalitat of Catalunya for a pre-doctoral fellowship F.I.
Funding Information:
Funding: This work was funded by the Spanish Ministry of Science and Innovation (grant BIO 2015-66356-R), by the University of Girona grant (MPCUdG2016/028) to R.P. and by the AGAUR-Generalitat de Catalunya grant (2014SGR0229) to R.d.L., and by grants from the Spanish Ministry of Economy and Competitiveness/ISCIII-FEDER (PI17/00199), and the Generalitat de Catalunya (2017-SGR-225) to P.N.
Publisher Copyright:
© 2020, MDPI AG. All rights reserved.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - 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 sLex and in most cases in sLea, 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.
AB - 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 sLex and in most cases in sLea, 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.
KW - Cell migration
KW - E-selectin
KW - Pancreatic ductal adenocarcinoma
KW - Sialyl-Lewis antigens
KW - α2,3-sialyltransferases
UR - http://www.scopus.com/inward/record.url?scp=85090180855&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85090180855&partnerID=8YFLogxK
U2 - 10.3390/ijms21176239
DO - 10.3390/ijms21176239
M3 - Article
C2 - 32872308
AN - SCOPUS:85090180855
VL - 21
SP - 1
EP - 24
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 17
M1 - 6239
ER -