title: 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.
authors.affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Woodcock
authors.affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia.
authors.forename: Carl
authors.initials: C
authors.lastname: Coolen
authors.affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia.
authors.forename: Katy L
authors.initials: KL
authors.lastname: Goodwin
authors.affiliation: Department of Chemistry and Biochemistry, Queens College of the City University of New York, Flushing, NY, USA.
authors.forename: Dong Jae
authors.initials: DJ
authors.lastname: Baek
authors.affiliation: Department of Chemistry and Biochemistry, Queens College of the City University of New York, Flushing, NY, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Bittman
authors.affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia.|School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Samuel
authors.affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia.|School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Pitson
authors.affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia.|School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Angel F
authors.initials: AF
authors.lastname: Lopez
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D006801:Humans; D019169:Jurkat Cells; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D015398:Signal Transduction; D013110:Sphingosine / Q000494:pharmacology
chemical_list: D048948:14-3-3 Proteins; D013110:Sphingosine
keywords: apoptosis; biochemistry; signal transduction; small molecules; sphingosine