A functional genomics approach to the mode of action of apratoxin A.
Nat Chem Biol
; 2(3): 158-67, 2006 Mar.
Article
em En
| MEDLINE
| ID: mdl-16474387
ABSTRACT
The cyanobacterial metabolite apratoxin A (1) demonstrates potent cytotoxicity against tumor cell lines by a hitherto unknown mechanism. We have used functional genomics to elucidate the molecular basis for this activity. Gene expression profiling and DNA content analysis showed that apratoxin A induces G1-phase cell cycle arrest and apoptosis. Cell-based functional assays with a genome-wide collection of expression cDNAs showed that ectopic induction of fibroblast growth factor receptor (FGFR) signaling attenuates the apoptotic activity of apratoxin A. This natural product inhibited phosphorylation and activation of STAT3, a downstream effector of FGFR signaling. It also caused defects in FGF-dependent processes during zebrafish development, with concomitant reductions in expression levels of the FGF target gene mkp3. We conclude that apratoxin A mediates its antiproliferative activity through the induction of G1 cell cycle arrest and an apoptotic cascade, which is at least partially initiated through antagonism of FGF signaling via STAT3.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ciclo Celular
/
Genômica
/
Depsipeptídeos
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Nat Chem Biol
Assunto da revista:
BIOLOGIA
/
QUIMICA
Ano de publicação:
2006
Tipo de documento:
Article
País de afiliação:
Estados Unidos