Glycosylation and cancer: A potential target for therapeutic intervention.

Abstract

e13507 Background: Aberrant glycosylation is a hallmark of cancer progression. Altered expression of glycosyltransferases and molecular facilitators within the ER and Golgi apparatus contributes to these changes. The tetraspanin are a family of molecular facilitators, expression of which have been shown to either promote or suppress cancer progression. CD151, a member of this family, modulates the glycosylation of its partner, the α3β1 integrin, affecting the integrin’s affinity towards its laminin ligand. Methods: We have characterised the glycosylation characteristics of CD151 and CD63 using glycosylation inhibitors and glycosidases to explore their patho-physiological role. Results: Inhibition of glucosidaseI/II resulted in the downregulation of CD151 and its partners, α3β1 and α6β1 integrins. 3D cell culture of the glioblastoma cell line (U87MG) in the presence of the inhibitor restrained its dendrite-like invasive growth. Similarly, the migration potential of the breast cancer cell line, MDA-MB-231, towards Lm332 decreased by 90% upon glycosylation inhibitor treatment. Since brain tumours have been shown to have elevated expression of α3β1 and Laminin332 our results suggest that glycosylation inhibitors might have a potential for investigation of therapeutic agents. Glyco-analysis of CD63 in MDA-231 cells indicated the presence of phosphomannosylated(PM) group, which might contribute to its role in lysosomal targeting. Compared to MDA-231, U87MG cells showed markedly reduced PM of CD63. Increased sialylation has previously been identified as a signature for brain metastasis in MDA-231 cells. Accordingly, comparison of CD63 in high and low sialylated populations of MDA-231 showed, upon sorting, showed similarity between the highly sialylated population of MDA-231 and U87MG. Conclusions: Using glycosylation inhibitors, we have identified a novel use for these compounds in down-regulating two major cancer associated integrins, α3β1 and α6β1. We have also uncovered a previously unknown glycomodification of CD63, phosphomannosylation which may affect the metastatic potential of cancer cells. Both findings suggest a potential for glycosylation inhibitors as part of cancer therapy.