Date Published: June 20, 2018
Publisher: Public Library of Science
Author(s): Tyler Keeley, Shengchen Lin, Daniel K. Lester, Eric K. Lau, Shengyu Yang, Marco Magalhaes.
The fucose salvage pathway is a two-step process in which mammalian cells transform L-fucose into GDP-L-fucose, a universal fucose donor used by fucosyltransferases to modify glycans. Emerging evidence indicates the fucose salvage pathway and the fucosylation of proteins are altered during melanoma progression and metastasis. However the underlying mechanisms are not completely understood. Here, we report that the fucose salvage pathway inhibits invadopodia formation and extracellular matrix degradation by promoting α-1,2 fucosylation. Chemically or genetically increasing the fucose salvage pathway decreases invadopodium numbers and inhibits the proteolytic activity of invadopodia in WM793 melanoma cells. Inhibiting fucosylation by depleting fucokinase abrogates L-fucose-mediated inhibition of invadopodia, suggesting dependence on the fucose salvage pathway. The inhibition of invadopodium formation by L-fucose or ectopically expressed FUK could be rescued by treatment with α-1,2, but not α-1,3/α-1,4 fucosidase, implicating an α-1,2 fucose linkage-dependent anti-metastatic effect. The expression of FUT1, an α-1,2 fucosyltransferase, is remarkably down-regulated during melanoma progression, and the ectopic expression of FUT1 is sufficient to inhibit invadopodium formation and ECM degradation. Our findings indicate that the fucose salvage pathway can inhibit invadopodium formation, and consequently, invasiveness in melanoma via α-1,2 fucosylation. Re-activation of this pathway in melanoma could be useful for preventing melanoma invasion and metastasis.
L-fucose is a 6-carbon sugar utilized by mammalian cells for glycosylation. Glycans can be modified by either core or branch fucosylation mediated by 13 different fucosyl transferases . The deregulation of fucosylation in cancer has been reported to regulate cancer cell proliferation, adhesion, and motility [2, 3]. In melanoma, the core-fucosylation (α-1,6 fucosylation) mediated by fucosyltransferase 8 (FUT8) was reported to promote melanoma progression , while branched fucosylation through the α-1,2 linkage inhibits melanoma progression [4, 5]. Mammalian cells may use either de novo synthesis pathway or the salvage pathway to provide GDP-L-fucose for fucosylation . It is recently reported that the expression of fucokinase (FUK), a key enzyme in the fucose salvage pathway, is remarkably down-regulated in metastatic melanoma, limiting GDP-L-fucose substrate availability . Treating melanoma cells with L-fucose or overexpression of FUK resulted in decreased migratory potential as well as an increase in cell surface fucosylation. Administration of L-fucose through water supplementation not only slowed tumor growth, but also inhibited lung metastases in a melanoma mouse model , suggesting that the fucose salvage pathway can be targeted to suppress melanoma invasion and metastasis. However, it is not clear how protein fucosylation inhibits melanoma invasion and metastasis.
The differential deregulation of fucosylation has been correlated with tumorigenesis and tumor progression in various cancers [5, 24–27]. More recently, a systemic glycomics study suggested that the role of glycosylation in melanoma progression could be linkage dependent .