Abstract
Neuroblastoma, a sympathetic nervous system tumor, accounts for 15% of cancer deaths in children. In contrast to most human tumors, p53 is rarely mutated in human primary neuroblastoma, suggesting impaired p53 activation in neuroblastoma. Various studies have shown correlations between fgf1 expression levels and both prognosis severity and tumor chemoresistance. As we previously showed that fibroblast growth factor 1 (FGF1) inhibited p53-dependent apoptosis in neuron-like PC12 cells, we initiated the study of the interaction between the FGF1 and p53 pathways in neuroblastoma. We focused on the activity of either extracellular FGF1 by adding recombinant rFGF1 in media, or of intracellular FGF1 by overexpression in human SH-SY5Y and mouse N2a neuroblastoma cell lines. In both cell lines, the genotoxic drug etoposide induced a classical mitochondrial p53-dependent apoptosis. FGF1 was able to inhibit p53-dependent apoptosis upstream of mitochondrial events in SH-SY5Y cells by both extracellular and intracellular pathways. Both rFGF1 addition and etoposide treatment increased fgf1 expression in SH-SY5Y cells. Conversely, rFGF1 or overexpressed FGF1 had no effect on p53-dependent apoptosis and fgf1 expression in neuroblastoma N2a cells. Using different FGF1 mutants (that is, FGF1K132E, FGF1S130A and FGF1S130D), we further showed that the C-terminal domain and phosphorylation of FGF1 regulate its intracrine anti-apoptotic activity in neuroblastoma SH-SY5Y cells. This study provides the first evidence for a role of an intracrine growth factor pathway on p53-dependent apoptosis in neuroblastoma, and could lead to the identification of key regulators involved in neuroblastoma tumor progression and chemoresistance.
Highlights
The fibroblast growth factor 1 (FGF1) is an oncogene, which regulates many cellular processes including cell proliferation, differentiation and survival.[1,2,3] FGF1 has been linked to tumor development, as it is upregulated in various cancers
In the neuronal-like PC12 cells, we previously showed that FGF1, which lacks a secretion peptide signal but contains a nuclear localization sequence (NLS), acts by an intracrine and nuclear pathway for both its neurotrophic activity and its p53-dependent cell death protection
To test the putative protective activity of FGF1 on p53-dependent cell death in neuroblastoma models, we examined the effect of adding recombinant FGF1 in the culture medium on SH-SY5Y and N2a cell lines after etoposide treatment
Summary
The fibroblast growth factor 1 (FGF1) is an oncogene, which regulates many cellular processes including cell proliferation, differentiation and survival.[1,2,3] FGF1 has been linked to tumor development, as it is upregulated in various cancers (breast, ovarian, gliomas and astrocytomas). 15% of cancer deaths in young children.[16] In contrast to most human tumors, human primary neuroblastoma are rarely mutated in p53,17 suggesting that the p53 oncosuppressive signaling cascade must be bypassed in these tumors by blocking the upstream activation of p53 (that is, by amplification of MDM2 or hypermethylation of p14ARF).[18] In most neuroblastoma cell lines, p53-dependent apoptosis can be induced by genotoxic or oxidative stress and/or by inhibition of survival growth factor pathways.[19,20,21,22,23,24] In these cells, genotoxic stress induces the classical mitochondrial apoptotic pathway as well as the death-receptor extrinsic apoptotic pathway
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