Basic Fibroblast Growth Factor-induced Cell Death Is Effected through Sustained Activation of p38MAPK and Up-regulation of the Death Receptor p75NTR

Abstract

Basic fibroblast growth factor (bFGF) induces cell death in cells of the Ewing's sarcoma family of tumors in vivo and in vitro.In this study we demonstrate that this is dependent on the rapid and sustained activation of (ESFT) 1 encompasses a group of malignancies, including Ewing's sarcoma, Askin's tumor of the chest wall, and peripheral primitive neuroectodermal tumor, which are thought to be of neural histogenesis (1-3). ESFT exhibit a common genetic rearrangement involving fusion of the 5Ј end of the EWS gene on chromosome 22 to the 3Ј portion of members of the Ets gene family of transcription factors. In over 90% of cases the Ets gene family member is fused to the Fli1 gene located on chromosome 11 (4). This results in the generation of a fusion gene, the protein product of which has been implicated in development of the transformed ESFT phenotype (5-7). ESFT typically arise in the bone or soft tissue of adolescents and young adults, ϳ15-30% of patients presenting with metastatic disease. The outcome for this group of patients is particularly poor despite the use of aggressive therapeutic regimes, emphasizing the need for new therapeutic strategies.A role for autocrine and/or paracrine growth factor survival loops in ESFT is well documented; the blockade of insulin-like growth factor/insulin-like growth factor receptor 1 (8 -11) or stem cell factor (SCF)/c-Kit (12, 13) circuits results in a decrease in ESFT cell number in both in vitro and in vivo models. Previous studies (14) have also suggested that a basic fibroblast growth factor (bFGF)/fibroblast growth factor receptor autocrine/paracrine survival loop may be important for the survival and proliferation of ESFT. However, we have found no evidence of such a survival loop, and we demonstrated recently that treatment of ESFT with bFGF results in the up-regulation of the death receptor p75NTR and induction of cell death (15, 16). The intracellular signaling pathways leading to the induction of cell death following exposure of ESFT cells to bFGF are unknown. Although our preliminary results have shown that incubation of ESFT cells with bFGF causes phosphorylation of fibroblast growth factor receptor 1 and activation of the downstream signaling molecules Ras and ERK (16), whether these events are important effectors of bFGF-induced cell death is not clear. Following receptor activation, phosphorylated tyrosines function as binding sites for a number of downstream adapter and signaling proteins, including the docking protein FRS2 that recruits several signal transduction molecules leading to activation of the mitogen-activated protein kinase (MAPK) cascade and the phosphatidylinositol 3-kinase-AKT anti-apoptotic pathway (17, 18). Recruitment of guanine nucleotide exchange factors (e.g. hSOS) leads to the conversion of the small GTPase Ras from an inactive GDP-bound state to an active GTP-bound state and activation of the extracellular signal-regulated kinase (ERK) pathway (19). Activation of the Ras-ERK pathway has been shown to mediate such diverse cellular...

The sensitivity of the Ewing's sarcoma family of tumours to fenretinide-induced cell death is increased by EWS-Fli1-dependent modulation of p38MAPK activity

“…Moreover, inhibition of p38 MAPK has previously been demonstrated by our laboratory to attenuate basic fibroblast growth factor (bFGF; Williamson et al, 2004) and fenretinideinduced cell death (Myatt et al, 2005), suggesting that this kinase is a critical effector of cell death in ESFT. Therefore, expression and phosphorylation of p38 MAPK and JNK following treatment with fenretinide was determined in siRNA-treated cells.…”

The cardioprotective effect of the low molecular weight isoform of fibroblast growth factor-2: The role of JNK signaling

“…The FGF2 LMW and HMW isoforms have different roles in MAPK activation. Evidence showed that administration of the FGF2 LMW isoform to a tumor cell line activated p38 MAPK and ERK, leading to cell death [33]. Overexpressing the FGF2 HMW isoform in pancreatic cells caused an increase in ERK activation [34].…”

Differential susceptibility to TRAIL of normal versus malignant human urothelial cells

“…32 This inhibitor has been used very extensively in the literature and has previously been shown to block p38 MAPK -mediated phosphorylation of ATF-2 in our laboratories. 33 Although both inhibitors dose-dependently increased TRAIL-induced death (Figure 6a), inhibition of NF-kB resulted in the highest degree of apoptosis in NHU cells, whereas in 253J cells, resistance was almost exclusively dependent on the p38 MAPK pathway (Figure 6a). Owing to the apparent association between susceptibility to TRAIL and loss of antiapoptotic proteins such as FLIP, we examined the possibility that changes in the expression of FLIP following combined treatment of urothelial cells with TRAIL and NF-kB/ p38 MAPK inhibitors could explain the differential apoptotic responses observed.…”