A functional genomics approach to the mode of action of apratoxin A

Hendrik Luesch*, Sumit K. Chanda, R. Marina Raya, Paul D. DeJesus, Anthony P. Orth, John R. Walker, Juan Carlos Izpisua Belmonte, Peter G. Schultz

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

120 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)158-167
Number of pages10
JournalNature Chemical Biology
Volume2
Issue number3
DOIs
StatePublished - Jan 1 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'A functional genomics approach to the mode of action of apratoxin A'. Together they form a unique fingerprint.

Cite this