Preferential Killing of PTEN-null Myelomas by PI3K Inhibitors Through Akt Pathway

Oncogene. 2003 Sep 18;22(40):6289-95. doi: 10.1038/sj.onc.1206718.

Abstract

We recently reported that internal deletion of PTEN tumor suppressor gene in OPM2 and Delta47 myeloma lines led to high Akt activation. Re-expression of PTEN induced strong apoptosis and growth inhibition. To understand the biologic importance of the phosphatidylinositol 3 kinase (PI3K)/Akt activation affected by PTEN deletion, we analysed apoptosis and growth inhibition by applying PI3K inhibitors to myeloma lines and by expressing Akt constructs. The PI3K inhibitors preferentially suppressed PTEN-null myeloma growth to those expressing PTEN, indicating that PI3K activation is more critical for growth and survival of those lines with PTEN mutations than others expressing a functional PTEN gene. Since PTEN-null myeloma lines exhibited much stronger Akt activation than PTEN-expressing cells in response to insulin-like growth factor I stimulation, we determined whether Akt could be responsible for PI3K-mediated cell survival and growth of PTEN-null myeloma lines. Expression of an active Akt, but not its kinase dead mutant, reversed wortmannin- and dexamethasone-induced apoptosis and growth inhibition in PTEN-null myeloma lines, suggesting that Akt lies downstream of PI3K for PTEN-null myeloma survival and dexamethasone resistance. In summary, we have provided evidence that PTEN-null myeloma cells are stringently dependent on the PI3K/Akt activation for cell survival. These results may provide a basis to treat myeloma patients with PI3K and Akt inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / pharmacology
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Butadienes / pharmacology
  • Cell Division / drug effects
  • Cell Survival
  • Chromones / pharmacology
  • Dexamethasone / pharmacology
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Gene Deletion
  • Genes, Tumor Suppressor
  • Humans
  • Insulin-Like Growth Factor I / pharmacology
  • Interleukin-6 / pharmacology
  • Morpholines / pharmacology
  • Multiple Myeloma / genetics
  • Multiple Myeloma / metabolism*
  • Nitriles / pharmacology
  • PTEN Phosphohydrolase
  • Phosphoinositide-3 Kinase Inhibitors*
  • Phosphoric Monoester Hydrolases / genetics*
  • Phosphoric Monoester Hydrolases / metabolism*
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism*
  • Wortmannin

Substances

  • Androstadienes
  • Antineoplastic Agents
  • Butadienes
  • Chromones
  • Enzyme Inhibitors
  • Interleukin-6
  • Morpholines
  • Nitriles
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Tumor Suppressor Proteins
  • U 0126
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Insulin-Like Growth Factor I
  • Dexamethasone
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Wortmannin