Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells
Abstract
Asparagine (N)-linked glycosylation is really a protein modification crucial for glycoprotein folding, stability, and cellular localization. To recognize small molecules that hinder new targets within this biosynthetic path, we initiated a cell-based high-throughput screen and lead-compound-optimization campaign that delivered a cell-permeable inhibitor, NGI-1. NGI-1 targets oligosaccharyltransferase (OST), a hetero-oligomeric enzyme that exists in multiple isoforms and transfers oligosaccharides to recipient proteins. In non-small-cell cancer of the lung cells, NGI-1 blocks cell-surface localization and signaling from the epidermal growth factor receptor (EGFR) glycoprotein, but selectively arrests proliferation in just individuals cell lines which are determined by EGFR (or fibroblast growth factor, FGFR) for survival. During these cell lines, OST inhibition causes cell-cycle arrest supported by induction of p21, autofluorescence, and cell morphology changes, all hallmarks of senescence. These results identify OST inhibition like a potential therapeutic method for treating receptor-tyrosine-kinase-dependent tumors and offers a compound probe for reversibly controlling N-linked glycosylation in mammalian NGI-1 cells.