Abstract
IntroductionProtein glycosylation is a post-translational event in which oligosaccharides (glycans) are attached to proteins; glycosylation events are mediated by glycosyltransferases and glycosidases. All cancer types studied so far have been shown to exhibit alterations in glycosylation affecting cell-cell adhesion, favouring cell migration and metastasis.The aim of this study was to evaluate whether changes in protein glycosylation affects the responsiveness of cancer cells to1 the chemotherapeutic agent doxorubicin (DXR);2 trastuzumab (Herceptin) interaction with HER2 and3 the responsiveness of cancer cells to growth factors (EGF and IGF-1).Material and methodsA range of cancer cell lines were initially investigated and SKBR-3 cells were selected for in-depth analysis by virtue of their HER2 +status. The interaction between trastuzumab and recombinant HER2 protein and cancer cell surfaces (on-rate/off-rate) was assessed using the Attana A200 quartz crystal microbalance (QCM) biosensor. The sensitivity of cells to DXR and to growth factors was evaluated using an MTT assay.Results and discussionsQCM biosensor analysis revealed that after deglycosylation the HER2 receptor was rendered more accessible to trastuzumab (deglycosylated cells Bmax: 6.83 Hz; glycosylated cells Bmax: 7.35 Hz). Maintenance of SKBR-3 cells in tunicamycin (an inhibitor of N-linked glycosylation) resulted in an increase in sensitivity to DXR (0.1 µM DXR p<0.001) and a decrease in sensitivity to IGF-1 alone and to IGF-1 supplemented with EGF (p<0.001).ConclusionThis report illustrates the importance of N-linked glycosylation in modulating the response of cancer cells to chemotherapeutic and biological treatments and it highlights the potential of glycosylation inhibitors as drugs worth further investigation for the treatment of cancer.
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