Destabilisation of dimeric 14-3-3 proteins as a novel approach to anti-cancer therapeutics
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Joanna M. Woodcock1, Carl Coolen1, Katy L. Goodwin1, Dong Jae Baek2, Robert Bittman2,**, Michael S. Samuel1,3, Stuart M. Pitson1,3,* and Angel F. Lopez1,3,*
1 Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia
2 Department of Chemistry and Biochemistry, Queens College of the City University of New York, Flushing, NY, USA
3 School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia
* These authors have contributed Equally to this work
Joanna M. Woodcock, email:
Keywords: biochemistry, signal transduction, sphingosine, apoptosis, small molecules
Received: March 24, 2015 Accepted: April 11, 2015 Published: May 04, 2015
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.
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