Inhibition of AKT survival pathway by a small molecule inhibitor in human endometrial cancer cells

Br J Cancer. 2004 Nov 15;91(10):1808-12. doi: 10.1038/sj.bjc.6602214.

Abstract

The PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumour suppressor is mutated in 40-50% of human endometrial cancers. PTEN exerts its effects in part via inhibition of the antiapoptotic protein AKT. We demonstrate that two endometrial cancer cell lines that harbour PTEN mutations, Ishikawa and RL95-2, have high levels of phosphorylated AKT and high AKT kinase activity. Two additional endometrial cancer cell lines that express wild-type PTEN, Hec1A and KLE, have little phosphorylated AKT and minimal demonstrable AKT kinase activity. We tested a potential inhibitor of the AKT pathway, API-59CJ-OMe, in these four cell lines. We found that API-59CJ-OMe inhibits AKT kinase activity and induces apoptosis in the Ishikawa and RL95-2 cell lines with high AKT activity, but has little effect on Hec1A and KLE cells without AKT activity. API-59CJ-OMe may therefore have therapeutic potential for those endometrial cancers that harbour PTEN mutations and AKT activation.

Publication types

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

MeSH terms

  • Apoptosis / drug effects
  • Cell Survival / drug effects
  • Ellipticines / pharmacology*
  • Endometrial Neoplasms / drug therapy
  • Endometrial Neoplasms / genetics
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Mutation
  • PTEN Phosphohydrolase
  • Phosphoric Monoester Hydrolases / genetics*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction / drug effects
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins / genetics*

Substances

  • 9-methoxy-2-methylellipticinium acetate
  • Ellipticines
  • Enzyme Inhibitors
  • Proto-Oncogene Proteins
  • Tumor Suppressor Proteins
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • PTEN protein, human