Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells

Cecilia Lopez-Sambrooks, Shiteshu Shrimal, Carol Khodier, Daniel P. Flaherty, Natalie Rinis, Jonathan C. Charest, Ningguo Gao, Peng Zhao, Lance Wells, Timothy A. Lewis, Mark A. Lehrman, Reid Gilmore, Jennifer E. Golden, Joseph N. Contessa

Research output: Contribution to journalArticle

23 Citations (Scopus)

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 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.

Original languageEnglish (US)
JournalNature Chemical Biology
DOIs
StateAccepted/In press - Oct 3 2016

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Neoplasms
Glycosylation
Epidermal Growth Factor Receptor
Glycoproteins
Cell Line
Fibroblast Growth Factors
Asparagine
Biosynthetic Pathways
Receptor Protein-Tyrosine Kinases
Cell Cycle Checkpoints
Oligosaccharides
Non-Small Cell Lung Carcinoma
dolichyl-diphosphooligosaccharide - protein glycotransferase
Protein Isoforms
Proteins
Enzymes
Therapeutics
Lead

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Lopez-Sambrooks, C., Shrimal, S., Khodier, C., Flaherty, D. P., Rinis, N., Charest, J. C., ... Contessa, J. N. (Accepted/In press). Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells. Nature Chemical Biology. https://doi.org/10.1038/nchembio.2194

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.; Lehrman, Mark A.; Gilmore, Reid; Golden, Jennifer E.; Contessa, Joseph N.

In: Nature Chemical Biology, 03.10.2016.

Research output: Contribution to journalArticle

Lopez-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 2016, 'Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells', Nature Chemical Biology. https://doi.org/10.1038/nchembio.2194
Lopez-Sambrooks C, Shrimal S, Khodier C, Flaherty DP, Rinis N, Charest JC et al. Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells. Nature Chemical Biology. 2016 Oct 3. https://doi.org/10.1038/nchembio.2194
Lopez-Sambrooks, Cecilia ; Shrimal, Shiteshu ; Khodier, Carol ; Flaherty, Daniel P. ; Rinis, Natalie ; Charest, Jonathan C. ; Gao, Ningguo ; Zhao, Peng ; Wells, Lance ; Lewis, Timothy A. ; Lehrman, Mark A. ; Gilmore, Reid ; Golden, Jennifer E. ; Contessa, Joseph N. / Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells. In: Nature Chemical Biology. 2016.
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