Knockdown of α2,3-Sialyltransferases Impairs Pancreatic Cancer Cell Migration, Invasion and E-selectin-Dependent Adhesion

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.

Sialyltransferase Inhibitors for the Treatment of Cancer Metastasis: Current Challenges and Future Perspectives

“…Results from the same group demonstrated that pancreatic adenocarcinoma tissues expressed high levels of ST3Gal-III and ST3Gal-IV. The observed pathologies are consistent with data gained in studies with cell models that showed that expression of sLe x , E-selectin adhesion, migration, and metastasis formation are promoted in ST3Gal-III- and ST3Gal-IV-overexpressing cells [ 37 , 38 ]. Furthermore, ST3Gal-III modulated breast cancer cell adhesion and invasion by altering sLe x expression, E-selectin binding capacity, and invasion-related protein expression including β1 integrin, MMP-2, and MMP-9 [ 39 ].…”

Aberrant Sialylation in Cancer: Biomarker and Potential Target for Therapeutic Intervention?

“…ST3GAL3 and ST3GAL4 have been shown to promote pancreatic cancer cell adhesion, motility and migration in vitro and to enhance metastatic potential in vivo [ 59 , 60 ]. Consistently, downregulation of either ST3GAL3 or ST3GAL4 decreased pancreatic cancer cell migration, invasion and E-selectin-dependent adhesion [ 61 ]. Gomes et al found that expression of ST3GAL4 in MKN45 gastric cancer cells resulted in enhanced synthesis of the sLex antigen and an increased invasive phenotype both in vitro and in vivo through the activation of c-Met [ 62 ].…”

The Cancer-Associated Antigens Sialyl Lewisa/x and Sda: Two Opposite Faces of Terminal Glycosylation

“…sLe x/a structures act as ligands for cell adhesion molecules of the selectin family, playing a fundamental role in leukocyte extravasation [ 83 ]. However, when overexpressed in cancer cells, they contribute to metastasis formation [ 84 ], particularly because they allow the interaction of circulating cancer cells with selectins expressed on endothelial cells [ 85 , 86 , 87 , 88 , 89 ]. This notion has been clearly demonstrated in vivo by showing that a CRC cell line injected subcutaneously in immunodeficient mice formed a much lower number of spontaneous lung metastases in E- and P-selectin-deficient mice [ 90 ].…”

“…Apart from the increased adhesion to selectin-expressing vessels, several studies indicate that sLe x/a structures increase motility, proliferation, and malignancy through selectin-independent mechanisms [ 87 , 88 , 96 , 97 , 98 ]. The colon cancer cell lines SW480 and SW620, which were derived from a primary colon cancer and a lymph node metastasis of the same patient, respectively, provide a good model of cells with different malignancy but a very similar genetic background.…”