TY - JOUR
T1 - Stapled peptide inhibitors of RAB25 target context-specific phenotypes in cancer
AU - Mitra, Shreya
AU - Montgomery, Jeffrey E.
AU - Kolar, Matthew J.
AU - Li, Gang
AU - Jeong, Kang J.
AU - Peng, Bo
AU - Verdine, Gregory L.
AU - Mills, Gordon B.
AU - Moellering, Raymond E.
N1 - Funding Information:
We thank the Broad Institute Chemical Biology Program for access to instrumentation; Jim Norman at the Beatson Institute for the gift of antibodies and plasmids; the Institute for Personalized Cancer Therapy (IPCT), and M.D. Anderson for RNA sequencing and data analysis. This work was funded in part by a sponsored research agreement with GlaxoSmithKline to G.B.M. and G.L.V.; National Cancer Institute (NCI) U01 CA168394 to G.B.M.; NCI R00CA175399 (R.E.M.); the Damon Runyon Cancer Research Foundation (DFS-08-14 to R.E.M.) and the V Foundation for Cancer Research (V2015-020 to R.E.M.).
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-017-00888-8
DO - 10.1038/s41467-017-00888-8
M3 - Article
C2 - 28939823
AN - SCOPUS:85029738433
SN - 2041-1723
VL - 8
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 660
ER -