Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/91652
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Type: | Journal article |
Title: | Destabilisation of dimeric 14-3-3 proteins as a novel approach to anti-cancer therapeutics |
Author: | Woodcock, J. Coolen, C. Goodwin, K. Baek, D. Bittman, R. Samuel, M. Pitson, S. Lopez, A. |
Citation: | Oncotarget, 2015; 6(16):14522-14536 |
Publisher: | Impact Journals |
Issue Date: | 2015 |
ISSN: | 1949-2553 1949-2553 |
Statement of Responsibility: | Joanna M. Woodcock, Carl Coolen, Katy L. Goodwin, Dong Jae Baek, Robert Bittman, Michael S. Samuel, Stuart M. Pitson and Angel F. Lopez |
Abstract: | 14-3-3 proteins play a pivotal role in controlling cell proliferation and survival, two commonly dysregulated hallmarks of cancers. 14-3-3 protein expression is enhanced in many human cancers and correlates with more aggressive tumors and poor prognosis, suggesting a role for 14-3-3 proteins in tumorigenesis and/or progression. We showed previously that the dimeric state of 14-3-3 proteins is regulated by the lipid sphingosine, a physiological inducer of apoptosis. As the functions of 14-3-3 proteins are dependent on their dimeric state, this sphingosine-mediated 14-3-3 regulation provides a possible means to target dimeric 14-3-3 for therapeutic effect. However, sphingosine mimics are needed that are not susceptible to sphingolipid metabolism. We show here the identification and optimization of sphingosine mimetics that render dimeric 14-3-3 susceptible to phosphorylation at a site buried in the dimer interface and induce mitochondrial-mediated apoptosis. Two such compounds, RB-011 and RB-012, disrupt 14-3-3 dimers at low micromolar concentrations and induce rapid down-regulation of Raf-MAPK and PI3K-Akt signaling in Jurkat cells. Importantly, both RB-011 and RB-012 induce apoptosis of human A549 lung cancer cells and RB-012, through disruption of MAPK signaling, reduces xenograft growth in mice. Thus, these compounds provide proof-of-principle for this novel 14-3-3-targeting approach for anti-cancer drug discovery. |
Keywords: | apoptosis biochemistry signal transduction small molecules sphingosine |
Rights: | This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
DOI: | 10.18632/oncotarget.3995 |
Published version: | http://dx.doi.org/10.18632/oncotarget.3995 |
Appears in Collections: | Aurora harvest 2 Medicine publications |
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hdl_91652.pdf | Published version | 3.78 MB | Adobe PDF | View/Open |
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