Inhibition of fucosylation in human invasive ductal carcinoma reduces E‐selectin ligand expression, cell proliferation, and ERK1/2 and p38 MAPK activation

Abstract

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.

DNA methylation landscape of triple-negative ductal carcinoma in situ (DCIS) progressing to the invasive stage in canine breast cancer

“…FUT5 is a gene involved in the fucosylation of glycans in circulating tumor cells leading to the initiation of tumor extravasation. Inhibition of fucosylation has been shown to reduce oncogenic properties of breast cancer; therefore, hypomethylation and subsequent activation of FUT5 to increase fucosylation could exacerbate oncogenic properties 65 .…”

The Long Noncoding RNA 150Rik Promotes Mesangial Cell Proliferation via miR-451/IGF1R/p38 MAPK Signaling in Diabetic Nephropathy

“…IGF1R is a protein and transmembrane tyrosine protein receptor which is involved in the IGF1/MAPK signalling pathway [48,49]. P38MAPK, an important member of the MAPK signalling pathway, can activate the MAPK signalling pathway [50][51][52][53], causing the proliferation of cells [54][55][56]. Moreover, our previous studies have shown that p38MAPK signalling is inhibited by miR-451 in early DN [15].…”

Role of fucosyltransferase IV in the migration and invasion of human melanoma cells

“…The addition of an α‐1,3/4‐linkage to N ‐acetylglucosamine (GlcNAc) in Gal‐GlcNAc is mediated by FUT3‐7 and FUT9‐11. FUT8 catalyzes the innermost asparagine‐linked (core) GlcNAc in N‐glycans . FUT4 catalyzes the α‐1,3 fucose linkage in Lewis x and Lewis y structures, which is associated with tumor proliferation, invasion, and metastasis .…”

“…FUT8 catalyzes the innermost asparagine‐linked (core) GlcNAc in N‐glycans . FUT4 catalyzes the α‐1,3 fucose linkage in Lewis x and Lewis y structures, which is associated with tumor proliferation, invasion, and metastasis . Increased FUT4 levels have been reported in multiple cancers, including acute myeloid leukemia, colon, and gastric and lung cancers .…”

“…12 FUT4 catalyzes the α-1,3 fucose linkage in Lewis x and Lewis y structures, which is associated with tumor proliferation, invasion, and metastasis. [12][13][14] Increased FUT4 levels have been reported in multiple cancers, including acute myeloid leukemia, 15 colon, 16 and gastric and lung cancers. 17,18 In addition, increased FUT4 expression has been shown to promote cell proliferation and metastasis while preventing apoptosis.…”