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Nat Chem Biol DOI:10.1038/nchembio.2194

Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells.

Publication TypeJournal Article
Year of Publication2016
AuthorsLopez-Sambrooks, C, Shrimal, S, Khodier, C, Flaherty, DP, Rinis, N, Charest, JC, Gao, N, Zhao, P, Wells, L, Lewis, TA, Lehrman, MA, Gilmore, R, Golden, JE, Contessa, JN
JournalNat Chem Biol
Date Published2016 Dec
KeywordsBenzamides, Cell Cycle Checkpoints, Cell Line, Tumor, Cell Proliferation, Cellular Senescence, Dose-Response Relationship, Drug, Enzyme Inhibitors, Hexosyltransferases, High-Throughput Screening Assays, Humans, Membrane Proteins, Molecular Structure, Receptor Protein-Tyrosine Kinases, Structure-Activity Relationship, Sulfonamides

Asparagine (N)-linked glycosylation is a protein modification critical for glycoprotein folding, stability, and cellular localization. To identify small molecules that inhibit new targets in this biosynthetic pathway, 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 lung cancer cells, NGI-1 blocks cell-surface localization and signaling of the epidermal growth factor receptor (EGFR) glycoprotein, but selectively arrests proliferation in only those cell lines that are dependent on EGFR (or fibroblast growth factor, FGFR) for survival. In these cell lines, OST inhibition causes cell-cycle arrest accompanied by induction of p21, autofluorescence, and cell morphology changes, all hallmarks of senescence. These results identify OST inhibition as a potential therapeutic approach for treating receptor-tyrosine-kinase-dependent tumors and provides a chemical probe for reversibly regulating N-linked glycosylation in mammalian cells.


Alternate JournalNat. Chem. Biol.
PubMed ID27694802
PubMed Central IDPMC5393272
Grant ListR01 GM043768 / GM / NIGMS NIH HHS / United States
U54 HG005032 / HG / NHGRI NIH HHS / United States
P41 GM103490 / GM / NIGMS NIH HHS / United States
U54 HG005031 / HG / NHGRI NIH HHS / United States
R01 GM038545 / GM / NIGMS NIH HHS / United States
KL2 TR001862 / TR / NCATS NIH HHS / United States
P30 CA016359 / CA / NCI NIH HHS / United States
R03 DA033178 / DA / NIDA NIH HHS / United States
R01 CA172391 / CA / NCI NIH HHS / United States