A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells

Cancer Cell. 2003 Dec;4(6):463-76. doi: 10.1016/s1535-6108(03)00303-9.

Abstract

The PI3K/PTEN/Akt signal transduction pathway plays a key role in many tumors. Downstream targets of this pathway include the Forkhead family of transcription factors (FOXO1a, FOXO3a, FOXO4). In PTEN null cells, FOXO1a is inactivated by PI3K-dependent phosphorylation and mislocalization to the cytoplasm, yet still undergoes nucleocytoplasmic shuttling. Since forcible localization of FOXO1a to the nucleus can reverse tumorigenicity of PTEN null cells, a high-content, chemical genetic screen for inhibitors of FOXO1a nuclear export was performed. The compounds detected in the primary screen were retested in secondary assays, and structure-function relationships were identified. Novel general export inhibitors were found that react with CRM1 as well as a number of compounds that inhibit PI3K/Akt signaling, among which are included multiple antagonists of calmodulin signaling.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus / drug effects*
  • Animals
  • Benzimidazoles / pharmacology
  • Benzothiazoles / pharmacology
  • Calmodulin / metabolism
  • Cell Nucleus / metabolism
  • DNA-Binding Proteins / metabolism*
  • Drug Design*
  • Enzyme Inhibitors / pharmacology*
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Karyopherins / metabolism
  • Models, Molecular
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoric Monoester Hydrolases / deficiency
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphorylation
  • Receptors, Cytoplasmic and Nuclear*
  • Signal Transduction / drug effects
  • Transcription Factors / metabolism*
  • Tumor Cells, Cultured

Substances

  • 5233705 compound
  • Benzimidazoles
  • Benzothiazoles
  • Calmodulin
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Karyopherins
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • exportin 1 protein
  • Phosphoric Monoester Hydrolases