Fibroblast growth factor and insulin-like growth factor differentially modulate the apoptosis and G1 arrest induced by anti-epidermal growth factor receptor monoclonal antibody

Oncogene. 2001 Apr 5;20(15):1913-22. doi: 10.1038/sj.onc.1204277.


DiFi human colon carcinoma cells are stimulated by the transforming growth factor-alpha (TGF-alpha)/epidermal growth factor (EGF) receptor autocrine loop. Exposure of DiFi cells to monoclonal antibody (mAb) 225, which blocks ligand-induced activation of the EGF receptor, induces G1 arrest and subsequent cell death via apoptosis. We investigated the signal pathways by which basic fibroblast growth factor (bFGF) and insulin-like growth factor-1 (IGF-1) modulate mAb 225-induced G1 arrest and apoptosis in DiFi cells. Both bFGF and IGF-1 activated the mitogen-activated protein kinase (MAPK) kinase (MEK) pathway in DiFi cells. Additionally, IGF-1 activated the phosphoinositide 3-kinase (PI-3K)/Akt pathway. Both bFGF and IGF-1 inhibited mAb 225-induced apoptosis; however, bFGF provided sustained protection against apoptosis, while the protection by IGF-1 was only temporary. Also, bFGF reversed the mAb 225-induced increase in the p27(Kip1) level, inhibition of cyclin-dependent kinase-2 (CDK-2) activity, dephosphorylation of the retinoblastoma (Rb) protein and the resultant G1 arrest of the cells. In contrast, IGF-1 did not reverse such effects by mAb 225. The prevention of mAb 225-induced G1 arrest and apoptosis in DiFi cells by bFGF was sensitive to the MEK/MAPK inhibitor PD98059 but not to the PI-3K inhibitor LY294002. In contrast, inhibition of apoptosis by IGF-1 in DiFi cells was sensitive only to LY294002 and not to PD98059. These results further our understanding of how mAb 225 induces apoptosis in DiFi cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / immunology*
  • Apoptosis / drug effects*
  • CDC2-CDC28 Kinases*
  • Chromones / pharmacology
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases / metabolism
  • ErbB Receptors / physiology*
  • Fibroblast Growth Factor 2 / pharmacology*
  • Flavonoids / pharmacology
  • G1 Phase / drug effects*
  • Humans
  • Insulin-Like Growth Factor I / pharmacology*
  • Mitogen-Activated Protein Kinases / metabolism
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / physiology
  • Protein-Serine-Threonine Kinases / metabolism
  • Tumor Cells, Cultured


  • Antibodies, Monoclonal
  • Chromones
  • Flavonoids
  • Morpholines
  • Fibroblast Growth Factor 2
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Insulin-Like Growth Factor I
  • Phosphatidylinositol 3-Kinases
  • ErbB Receptors
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases
  • Mitogen-Activated Protein Kinases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one