Inhibitor of ppGalNAc-T3-mediated O-glycosylation blocks cancer cell invasiveness and lowers FGF23 levels

  1. Lina Song
  2. Adam Linstedt  Is a corresponding author
  1. Carnegie Mellon University, United States

Abstract

Small molecule inhibitors of site-specific O-glycosylation by the polypeptide N-acetylgalactosaminyltransferase (ppGalNAc-T) family are currently unavailable but hold promise as therapeutics, especially if selective against individual ppGalNAc-T isozymes. To identify a compound targeting the ppGalNAc-T3 isozyme, we screened libraries to find compounds that act on a cell-based fluorescence sensor of ppGalNAc-T3 but not on a sensor of ppGalNAc-T2. This identified a hit that subsequent in vitro analysis showed directly binds and inhibits purified ppGalNAc-T3 with no detectable activity against either ppGalNAc-T2 or ppGalNAc-T6. Remarkably, the inhibitor was active in two medically relevant contexts. In cell culture, it opposed increased cancer cell invasiveness driven by upregulated ppGalNAc-T3 suggesting the inhibitor might be anti-metastatic. In cells and mice, it blocked ppGalNAc-T3-mediated glycan-masking of FGF23 thereby increasing its cleavage, a possible treatment of chronic kidney disease. These findings establish a pharmacological approach for the ppGalNAc-transferase family and suggest that targeting specific ppGalNAc-transferases will yield new therapeutics.

Article and author information

Author details

  1. Lina Song

    Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Adam Linstedt

    Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, United States
    For correspondence
    linstedt@andrew.cmu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0754-1638

Funding

National Institutes of Health (1R21DE026714)

  • Adam Linstedt

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Protocols, handling, and care of the mice conformed to protocols approved by the Institutional Animal Care and Use Committee of Carnegie Mellon University.(CMU IACUC protocol AS16-005).

Reviewing Editor

  1. Christopher G Burd, Yale School of Medicine, United States

Publication history

  1. Received: December 8, 2016
  2. Accepted: March 30, 2017
  3. Accepted Manuscript published: March 31, 2017 (version 1)
  4. Version of Record published: April 27, 2017 (version 2)
  5. Version of Record updated: May 12, 2017 (version 3)

Copyright

© 2017, Song & Linstedt

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Lina Song
  2. Adam Linstedt
(2017)
Inhibitor of ppGalNAc-T3-mediated O-glycosylation blocks cancer cell invasiveness and lowers FGF23 levels
eLife 6:e24051.
https://doi.org/10.7554/eLife.24051

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