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Identifying Protein-protein Interaction Sites Using Peptide Arrays
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Stapled peptide inhibitors of RAB25 target context-specific phenotypes in cancer

Shreya Mitra1, Jeffrey E Montgomery2,3, Matthew J Kolar4,5

  • 1Department of Systems Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.

Nature Communications
|September 24, 2017
PubMed

Insights

Researchers developed stabilized peptides to target RAB25, a small GTPase involved in cancer. These peptides inhibit cancer cell migration and proliferation in a context-dependent manner, validating new chemical probes for RAB-family proteins.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The small GTPase RAB25 plays a dual role in cancer, acting as both a pro-oncogenic and anti-oncogenic factor depending on the cellular context.
  • Understanding RAB25's context-specific functions is crucial for developing targeted cancer therapies.

Purpose of the Study:

  • To develop novel, cell-active chemical probes targeting RAB25.
  • To investigate the functional impact of targeting RAB25:FIP complex formation on cancer cell phenotypes.

Main Methods:

  • Development of all-hydrocarbon stabilized peptides derived from RAB-binding FIP-family proteins.
  • Treatment of various cancer cell lines with optimized stapled peptides (e.g., RFP14).
  • Assessment of cell migration, proliferation, and transcriptional profiling.

Main Results:

  • Optimized stapled peptides demonstrated enhanced stability, binding affinity, and cell permeability compared to unmodified peptides.
  • The stapled peptide RFP14 inhibited cancer cell migration and proliferation in cell lines where RAB25 is pro-oncogenic, in a RAB25-dependent manner.
  • RFP14 treatment augmented pro-oncogenic phenotypes in breast cancer cells where RAB25 acts as a tumor suppressor, and altered gene expression profiles.

Conclusions:

  • Validated the first cell-active chemical probes targeting RAB-family proteins, specifically RAB25.
  • Demonstrated that targeting RAB25 with stabilized peptides can modulate context-specific oncogenic phenotypes.
  • These findings support the role of RAB25 in regulating diverse cancer cell behaviors and offer potential therapeutic strategies.

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