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Destabilisation of dimeric 14-3-3 proteins as a novel approach to anti-cancer therapeutics.

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.

SUBMITTER: Woodcock JM

PROVIDER: S-EPMC4546484 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Destabilisation of dimeric 14-3-3 proteins as a novel approach to anti-cancer therapeutics.

Woodcock Joanna M JM Coolen Carl C Goodwin Katy L KL Baek Dong Jae DJ Bittman Robert R Samuel Michael S MS Pitson Stuart M SM Lopez Angel F AF

Oncotarget 20150601 16

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 pro ...[more]

PMID: 25971334

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Dataset Information

Destabilisation of dimeric 14-3-3 proteins as a novel approach to anti-cancer therapeutics.

Publications

Destabilisation of dimeric 14-3-3 proteins as a novel approach to anti-cancer therapeutics.

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