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

Shreya Mitra, Jeffrey E. Montgomery, Matthew J. Kolar, Gang Li, Kang J. Jeong, Bo Peng, Gregory L. Verdine, Gordon Mills, Raymond E. Moellering

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Article number660
JournalNature Communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017
Externally publishedYes

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phenotype
inhibitors
peptides
cancer
Phenotype
Peptides
proteins
Neoplasms
Cells
effectors
Proteins
Monomeric GTP-Binding Proteins
structural stability
Hydrocarbons
cells
cultured cells
breast
affinity
Tumors
Permeability

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Mitra, S., Montgomery, J. E., Kolar, M. J., Li, G., Jeong, K. J., Peng, B., ... Moellering, R. E. (2017). Stapled peptide inhibitors of RAB25 target context-specific phenotypes in cancer. Nature Communications, 8(1), [660]. https://doi.org/10.1038/s41467-017-00888-8

Stapled peptide inhibitors of RAB25 target context-specific phenotypes in cancer. / Mitra, Shreya; Montgomery, Jeffrey E.; Kolar, Matthew J.; Li, Gang; Jeong, Kang J.; Peng, Bo; Verdine, Gregory L.; Mills, Gordon; Moellering, Raymond E.

In: Nature Communications, Vol. 8, No. 1, 660, 01.12.2017.

Research output: Contribution to journalArticle

Mitra, S, Montgomery, JE, Kolar, MJ, Li, G, Jeong, KJ, Peng, B, Verdine, GL, Mills, G & Moellering, RE 2017, 'Stapled peptide inhibitors of RAB25 target context-specific phenotypes in cancer', Nature Communications, vol. 8, no. 1, 660. https://doi.org/10.1038/s41467-017-00888-8
Mitra, Shreya ; Montgomery, Jeffrey E. ; Kolar, Matthew J. ; Li, Gang ; Jeong, Kang J. ; Peng, Bo ; Verdine, Gregory L. ; Mills, Gordon ; Moellering, Raymond E. / Stapled peptide inhibitors of RAB25 target context-specific phenotypes in cancer. In: Nature Communications. 2017 ; Vol. 8, No. 1.
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