Abstract
Glycosylation is recognized as one of the most common modifications on proteins. Recent studies have shown that aberrant expression of α (1,6) fucosyltransferase (FUT8), which catalyzes the transfer of fucose from GDP-fucose to core-GlcNAc of the N-linked glycoproteins, modulates cellular behavior that could lead to the development of aggressive prostate cancer. While the relationship between the abnormal expression of FUT8 and glycoprotein fucosylation in different prostate cancer cells has been demonstrated, there is no evidence that shows dysregulated fucosylation might be involved in prostate cancer progression from androgen-dependent to castration-resistant prostate cancer. In this study, using a proteomics approach, we analyzed androgen-dependent and androgen-resistant LAPC4 cells and identified FUT8 to be significantly overexpressed in the androgen-resistant LAPC4 cells. These findings were independently confirmed in LAPC4 cells that were treated with non-steroidal anti-androgen (bicalutamide) and in the in vivo castrated tumor xenograft models. Similarly, we also demonstrated that overexpression of FUT8 might be responsible for the decreased PSA expression in prostate cancer specimens. To our knowledge, this is the first study reporting the functional role of fucosylated enzyme in the development of castration-resistant prostate cancer.
Highlights
Prostate cancer is the most common and the second leading cause of cancer death in men in the United States [1]
The wild-type LAPC4 prostate cancer cell line was continuously cultured in charcoal dextran-stripped FBS-containing medium for more than 6 months to obtain androgenresistant LAPC4-AI cells as shown by schematics (Fig. 1a)
We evaluated the androgen receptor (AR) status of these cells by imunofluorescence (IF) microscopy and compared the AR localization between the LAPC4-AI grown in cFBS-containing medium and the wild-type LAPC4 cells that were grown in normal FBS-containing media supplemented with 1 nM of synthetic androgens (R1881)
Summary
Prostate cancer is the most common and the second leading cause of cancer death in men in the United States [1]. Resistant phenotype which is fatal [3] This transformation from a clinically localized hormone-dependent state to the androgen-resistant phenotype may involve changes in androgen receptor (AR) and associated pathways [4, 5]. Aberrant fucosylation, which results from the deficiency or overexpression of fucosyltransferases (FUTs), is associated with a variety of human diseases, including cancers [7, 8]. Unlike other FUTs that are functionally redundant, the α (1,6) fucosyltransferase (FUT8) is the only enzyme responsible for the α 1,6-linked (core) fucosylation that adds fucose to the inner most GlcNAc of an N-linked glycan [9]. Lack of the core fucose on these receptors leads to a marked reduction in ligand-binding ability and downstream signaling. An increase in core fucosylation on E-cadherin has been shown to strengthen cell–cell adhesion [17]
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