Basic fibroblast growth factor (bFGF)-induced cell death is mediated through a caspase-dependent and p53-independent cell death receptor pathway

Oncogene. 2002 Jan 24;21(5):809-24. doi: 10.1038/sj.onc.1205128.

Abstract

The mechanism of bFGF-induced cell death in tumours of the Ewing's sarcoma family (ESFT) has been investigated. bFGF-induces phosphorylation of FGFr 1 and activation of Ras/ERK in ESFT cells that die when exposed to bFGF. Induction of cell death was associated with activation of both initiator (caspases-2, -8 and -10) and effector (caspases-3, -6 and -7) caspases. Moreover, the general caspase inhibitor Z-VAD-FMK protected cells from bFGF-induced cell death. After treatment with bFGF, a loss of mitochondrial transmembrane potential was accompanied by down-regulation of Bcl-2. However, the observed cell death was not associated with release of cytochrome c from the mitochondria. Furthermore, expression of wild-type p53 was not required for bFGF-induced cell death. These observations suggest that bFGF-induced cell death may be mediated through a cell death receptor mechanism, supported by up-regulation of the p75 neurotrophin receptor. bFGF-induced cell death was associated with up-regulation of p21 and p53, down-regulation of PCNA and cyclin A and a decrease in active pRb1, changes consistent with accumulation of cells in G1. These data demonstrate that bFGF-induced cell death is effected through a caspase-dependent and p53-independent mechanism, that may be mediated through a cell death receptor pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Neoplasms / metabolism*
  • Bone Neoplasms / pathology
  • Caspases / physiology*
  • Cell Count
  • Cell Cycle / drug effects
  • Cell Death*
  • Cell Line
  • Fibroblast Growth Factor 2 / pharmacology*
  • Humans
  • Mice
  • Mitochondria / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptor, Nerve Growth Factor
  • Receptors, Fibroblast Growth Factor / metabolism
  • Receptors, Nerve Growth Factor / metabolism
  • Sarcoma, Ewing / metabolism*
  • Sarcoma, Ewing / pathology
  • Signal Transduction
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / physiology

Substances

  • Proto-Oncogene Proteins c-bcl-2
  • Receptor, Nerve Growth Factor
  • Receptors, Fibroblast Growth Factor
  • Receptors, Nerve Growth Factor
  • Tumor Suppressor Protein p53
  • Fibroblast Growth Factor 2
  • FGFR1 protein, human
  • Fgfr1 protein, mouse
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Fibroblast Growth Factor, Type 1
  • Mitogen-Activated Protein Kinases
  • Caspases
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)