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Oligosaccharyltransferase Inhibition Induces Senescence in RTK-Driven Tumor Cells
Lopez-Sambrooks, Cecilia Shrimal, Shiteshu Khodier, Carol Flaherty, Daniel P. Rinis, Natalie Charest, Jonathan C. Gao, Ningguo Zhao, Peng Wells, Lance Lewis, Timothy A.
Lopez-Sambrooks, Cecilia
Shrimal, Shiteshu
Khodier, Carol
Flaherty, Daniel P.
Rinis, Natalie
Charest, Jonathan C.
Gao, Ningguo
Zhao, Peng
Wells, Lance
Lewis, Timothy A.
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Abstract
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 the 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 EGFR glycoprotein, but selectively arrests proliferation in only those cell lines that are dependent on EGFR (or FGFR) for survival. In these cell lines OST inhibition causes cell cycle arrest accompanied by induction of p21, autofluorescence, and changes in cell morphology; 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.
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2016-12
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Nature Publishing Group
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Lopez-Sambrooks, C., Shrimal, S., Khodier, C., Flaherty, D. P., Rinis, N., Charest, J. C., … Contessa, J. N. (2016). Oligosaccharyltransferase Inhibition Induces Senescence in RTK-Driven Tumor Cells. Nature Chemical Biology, 12(12), 1023–1030. http://doi.org/10.1038/nchembio.2194