title: Basic fibroblast growth factor (bFGF)-induced cell death is mediated through a caspase-dependent and p53-independent cell death receptor pathway.
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.
authors.affiliation: Candlelighter's Children's Cancer Research Unit, ICRF Cancer Medicine Research Unit, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: Georgina
authors.initials: G
authors.lastname: Westwood
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Dibling
authors.forename: Darren
authors.initials: D
authors.lastname: Cuthbert-Heavens
authors.forename: Susan A
authors.initials: SA
authors.lastname: Burchill
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology; D020169:Caspases / Q000502:physiology*; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death; D002460:Cell Line; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020800:Receptor, Nerve Growth Factor; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D020800:Receptor, Nerve Growth Factor; D017468:Receptors, Fibroblast Growth Factor; D017475:Receptors, Nerve Growth Factor; D016159:Tumor Suppressor Protein p53; D016222:Fibroblast Growth Factor 2; C496348:FGFR1 protein, human; C496349:Fgfr1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)