Mannose glycosylation is an integral step for human NIS localization and function in breast cancer cells

Abstract

Chasing an intriguing biological question on the disparity of sodium iodide symporter (NIS or SLC5A5) expression and function in clinical scenario of breast cancer (BC), this study addresses key molecular defects involved. Human NIS expression is primarily recorded as a cytoplasmic protein, thus limiting its scope for targeted radio-iodine therapy. While developing NIS transgene over-expressing MCF-7 breast adenocarcinoma, a few unique clonal derivatives show predominant expression in plasma membrane, whereas majority others show cytosolic expression over long passages. The membrane lineage shows un-perturbed dynamic trafficking of NIS through secretory pathway organelles, when compared to cytoplasmic or parental cells. Further, treatment of membrane cells with specific glycosylation inhibitors highlights the importance of inherent glycosylation processing. The 84 gene signature glycosylation RT-Profiler array reveals that membrane clones cluster separately from the rest. Further, role of three differentially expressed genes i.e. MAN1B1, MAN1A1 and MAN2A1 in regulation of NIS localization is confirmed by RNA interference. Thus, for the first time this study shows the important role of mannosidase in N-glycosylation processing for proper trafficking of NIS to the plasma membrane in BC cells.