TY - JOUR
T1 - Targeting aberrant sialylation in cancer cells using a fluorinated sialic acid analog impairs adhesion, migration, and in vivo tumor growth
AU - Büll, Christian
AU - Boltje, Thomas J
AU - Wassink, Melissa
AU - de Graaf, Annemarie M A
AU - van Delft, Floris L
AU - den Brok, Martijn H
AU - Adema, Gosse J
N1 - ©2013 AACR.
PY - 2013/10
Y1 - 2013/10
N2 - Cancer cells decorate their surface with a dense layer of sialylated glycans by upregulating the expression of sialyltransferases and other glycogenes. Although sialic acids play a vital role in many biologic processes, hypersialylation in particular has been shown to contribute to cancer cell progression and metastasis. Accordingly, selective strategies to interfere with sialic acid synthesis might offer a powerful approach in cancer therapy. In the present study, we assessed the potential of a recently developed fluorinated sialic acid analogue (P-3Fax-Neu5Ac) to block the synthesis of sialoglycans in murine melanoma cells and the consequences on cell adhesion, migration, and in vivo growth. The results showed that P-3Fax-Neu5Ac readily caused depletion of a2,3-/a2,6-linked sialic acids in B16F10 cells for several days. Long-term inhibition of sialylation for 28 days was feasible without affecting cell viability or proliferation. Moreover, P-3Fax-Neu5Ac proved to be a highly potent inhibitor of sialylation even at high concentrations of competing sialyltransferase substrates. P-3Fax-Neu5Ac-treated cancer cells exhibited impaired binding to poly-L-lysine, type I collagen, and fibronectin and diminished migratory capacity. Finally, blocking sialylation of B16F10 tumor cells with this novel sialic acid analogue reduced their growth in vivo. These results indicate that P-3Fax-Neu5Ac is a powerful glycomimetic capable of inhibiting aberrant sialylation that can potentially be used for anticancer therapy.
AB - Cancer cells decorate their surface with a dense layer of sialylated glycans by upregulating the expression of sialyltransferases and other glycogenes. Although sialic acids play a vital role in many biologic processes, hypersialylation in particular has been shown to contribute to cancer cell progression and metastasis. Accordingly, selective strategies to interfere with sialic acid synthesis might offer a powerful approach in cancer therapy. In the present study, we assessed the potential of a recently developed fluorinated sialic acid analogue (P-3Fax-Neu5Ac) to block the synthesis of sialoglycans in murine melanoma cells and the consequences on cell adhesion, migration, and in vivo growth. The results showed that P-3Fax-Neu5Ac readily caused depletion of a2,3-/a2,6-linked sialic acids in B16F10 cells for several days. Long-term inhibition of sialylation for 28 days was feasible without affecting cell viability or proliferation. Moreover, P-3Fax-Neu5Ac proved to be a highly potent inhibitor of sialylation even at high concentrations of competing sialyltransferase substrates. P-3Fax-Neu5Ac-treated cancer cells exhibited impaired binding to poly-L-lysine, type I collagen, and fibronectin and diminished migratory capacity. Finally, blocking sialylation of B16F10 tumor cells with this novel sialic acid analogue reduced their growth in vivo. These results indicate that P-3Fax-Neu5Ac is a powerful glycomimetic capable of inhibiting aberrant sialylation that can potentially be used for anticancer therapy.
KW - Animals
KW - Cell Adhesion/drug effects
KW - Cell Movement/drug effects
KW - Cell Proliferation/drug effects
KW - Cell Survival/drug effects
KW - Fluorine/chemistry
KW - Humans
KW - Melanoma, Experimental/drug therapy
KW - Mice
KW - N-Acetylneuraminic Acid/analogs & derivatives
KW - Polysaccharides/biosynthesis
KW - Sialic Acids/pharmacology
U2 - 10.1158/1535-7163.mct-13-0279
DO - 10.1158/1535-7163.mct-13-0279
M3 - Journal article
C2 - 23974695
SN - 1535-7163
VL - 12
SP - 1935
EP - 1946
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 10
ER -
