Receptor tyrosine kinase and phosphoinositide-3 kinase signaling in malignant mesothelioma

J Thorac Cardiovasc Surg. 2005 Aug;130(2):393-400. doi: 10.1016/j.jtcvs.2004.11.029.


Objective: The phosphoinositide-3 kinase signaling pathway is implicated in the development of malignancy and promotes cell-cycle progression and resistance to apoptosis. Malignant mesothelioma tumor specimens demonstrate high levels of the phosphoinositide-3 kinase downstream mediator phosphorylated Akt. Exposure of mesothelioma cell lines to LY294002, a phosphoinositide-3 kinase inhibitor, results in apoptotic cell death and decreased phosphorylated Akt in vitro and tumor burden reduction in vivo. Phosphoinositide-3 kinase is activated by cell-surface receptor tyrosine kinases. We sought to determine which receptors are present in mesothelioma and their role in cellular survival and phosphoinositide-3 kinase signaling.

Methods: Western blot analysis was performed to determine the relative expression of epidermal growth factor receptor, insulin-like growth factor receptor, and platelet-derived growth factor receptor in the mesothelioma cell lines I-45 and REN and the mesothelial line Met5a. After exposure of mesothelioma lines to kinase inhibitors, a cell viability assay was performed, cell-cycle analysis was performed to determine the percentage of apoptosis, and Western blot analysis was performed for phosphorylated Akt.

Results: Inhibition of epidermal growth factor receptor resulted in apoptotic cell death and Akt hypophosphorylation in mesothelioma cell lines. Insulin-like growth factor receptor inhibition led to apoptotic cell death without affecting Akt phosphorylation. Platelet-derived growth factor receptor inhibition did not affect cellular survival or phosphoinositide-3 kinase signaling.

Conclusion: In malignant mesothelioma constitutive activation of phosphoinositide-3 kinase/Akt results in cellular survival and contributes to the malignant phenotype. We have demonstrated that epidermal growth factor receptor inhibition leads to apoptotic cell death through downregulation of phosphoinositide-3 kinase signaling in mesothelioma cell lines, whereas insulin-like growth factor receptor inhibition leads to apoptosis independent of phosphoinositide-3 kinase. Epidermal growth factor receptor, insulin-like growth factor receptor, and phosphoinositide-3 kinase inhibition might be clinically relevant in malignant mesothelioma.

MeSH terms

  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chromones / pharmacology*
  • ErbB Receptors / drug effects
  • Humans
  • Mesothelioma / drug therapy*
  • Mesothelioma / physiopathology
  • Morpholines / pharmacology*
  • Phosphatidylinositol 3-Kinases / drug effects*
  • Protein Kinase Inhibitors / pharmacology*
  • Receptor Protein-Tyrosine Kinases / drug effects*
  • Receptors, Platelet-Derived Growth Factor / drug effects
  • Receptors, Somatomedin / drug effects
  • Signal Transduction / drug effects


  • Chromones
  • Morpholines
  • Protein Kinase Inhibitors
  • Receptors, Somatomedin
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Phosphatidylinositol 3-Kinases
  • ErbB Receptors
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Platelet-Derived Growth Factor