A functional genomics approach to the mode of action of apratoxin A.
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.
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. luesch@cop.ufl.edu
Hendrik
H
Luesch
Sumit K
SK
Chanda
R Marina
RM
Raya
Paul D
PD
DeJesus
Anthony P
AP
Orth
John R
JR
Walker
Juan Carlos
JC
Izpisúa Belmonte
Peter G
PG
Schultz
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D047630:Depsipeptides / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D023281:Genomics / Q000379:methods*; D006801:Humans; D066298:In Vitro Techniques; D008968:Molecular Conformation; D010766:Phosphorylation; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D015027:Zebrafish / Q000196:embryology
D047630:Depsipeptides; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C442201:apratoxin A; D005346:Fibroblast Growth Factors