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    Oligosaccharyltransferase Inhibition Induces Senescence in RTK-Driven Tumor Cells

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    Flaherty_2016.pdf (1.309Mb)
    Issue Date
    2016-12
    Author
    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.
    Publisher
    Nature Publishing Group
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
    Metadata
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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.
    URI
    http://hdl.handle.net/1808/24114
    DOI
    https://doi.org/10.1038/nchembio.2194
    Collections
    • Chemistry Scholarly Works [600]
    Citation
    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

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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