Knockdown of α2,3-sialyltransferases impairs pancreatic cancer cell migration, invasion and e-selectin-dependent adhesion

Pedro Enrique Guerrero, Laura Miró, Bin S. Wong, Anna Massaguer, Neus Martínez-Bosch, Rafael de Llorens, Pilar Navarro, Konstantinos Konstantopoulos, Esther Llop, Rosa Peracaula

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number6239
Pages (from-to)1-24
Number of pages24
JournalInternational journal of molecular sciences
Volume21
Issue number17
DOIs
StatePublished - Sep 1 2020

Keywords

  • Cell migration
  • E-selectin
  • Pancreatic ductal adenocarcinoma
  • Sialyl-Lewis antigens
  • α2,3-sialyltransferases

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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