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Stapled peptide inhibitors of RAB25 target context-specific phenotypes in cancer

Author

Listed:
  • Shreya Mitra

    (University of Texas M.D. Anderson Cancer Center)

  • Jeffrey E. Montgomery

    (The University of Chicago
    Institute for Genomics and Systems Biology, The University of Chicago)

  • Matthew J. Kolar

    (Harvard University
    Harvard University)

  • Gang Li

    (The University of Chicago
    Institute for Genomics and Systems Biology, The University of Chicago)

  • Kang J. Jeong

    (University of Texas M.D. Anderson Cancer Center)

  • Bo Peng

    (University of Texas M.D. Anderson Cancer Center)

  • Gregory L. Verdine

    (Harvard University
    Harvard University)

  • Gordon B. Mills

    (University of Texas M.D. Anderson Cancer Center)

  • Raymond E. Moellering

    (The University of Chicago
    Institute for Genomics and Systems Biology, The University of Chicago)

Abstract

Recent evidence has established a role for the small GTPase RAB25, as well as related effector proteins, in enacting both pro-oncogenic and anti-oncogenic phenotypes in specific cellular contexts. Here we report the development of all-hydrocarbon stabilized peptides derived from the RAB-binding FIP-family of proteins to target RAB25. Relative to unmodified peptides, optimized stapled peptides exhibit increased structural stability, binding affinity, cell permeability, and inhibition of RAB25:FIP complex formation. Treatment of cancer cell lines in which RAB25 is pro-oncogenic with an optimized stapled peptide, RFP14, inhibits migration, and proliferation in a RAB25-dependent manner. In contrast, RFP14 treatment augments these phenotypes in breast cancer cells in which RAB25 is tumor suppressive. Transcriptional profiling identified significantly altered transcripts in response to RAB25 expression, and treatment with RFP14 opposes this expression profile. These data validate the first cell-active chemical probes targeting RAB-family proteins and support the role of RAB25 in regulating context-specific oncogenic phenotypes.

Suggested Citation

  • Shreya Mitra & Jeffrey E. Montgomery & Matthew J. Kolar & Gang Li & Kang J. Jeong & Bo Peng & Gregory L. Verdine & Gordon B. Mills & Raymond E. Moellering, 2017. "Stapled peptide inhibitors of RAB25 target context-specific phenotypes in cancer," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00888-8
    DOI: 10.1038/s41467-017-00888-8
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    Cited by:

    1. Ammu Prasanna Kumar & Suryani Lukman, 2018. "Allosteric binding sites in Rab11 for potential drug candidates," PLOS ONE, Public Library of Science, vol. 13(6), pages 1-46, June.

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