Fibroblast growth factor‐2 over‐rides insulin‐like growth factor‐I induced proliferation and cell survival in human neuroblastoma cells

Abstract

The insulin-like growth factor (IGF) system is a key regulator of cell growth, survival and differentiation, and these functions are co-modulated by other growth factors including fibroblast growth factor-2 (FGF-2). To investigate IGF/FGF interactions in neuronal cells, we employed neuroblastoma cells (SK-N-MC). In serum free conditions proliferation of the SK-N-MC cells was promoted by IGF-I (25 ng/ml), but blunted by FGF-2 (50 ng/ml). IGF-I-induced proliferation was abolished in the presence of FGF-2 even when IGF-I was used at 100 ng/ml. In addition to our previously described FGF-2 induced proteolytic cleavage of IGFBP-2, we found that FGF-2 increased IGFBP-6 levels in conditioned medium (CM) without affecting IGFBP-6 mRNA abundance. Modulation of IGFBP-2 and -6 levels were not significant mechanisms involved in the blockade of IGF-I action since the potent IGF-I analogues [QAYL]IGF-I and des(1-3)IGF-I (minimal IGFBP affinity) were unable to overcome FGF-2 inhibition of cell proliferation. FGF-2 treated cells showed morphological differentiation expressing the TUJ1 neuronal marker while cells treated with IGF-I alone showed no morphological change. When IGF-I was combined with FGF-2, however, cell morphology was indistinguishable from that seen with FGF-2 alone. FGF-2 inhibited proliferation and enhanced differentiation was also associated with a 70% increase in cell death. Although IGF-I alone was potently anti-apoptotic (60% decreased), IGF-I was unable to prevent apoptosis when administrated in combination with FGF-2. Gene-array analysis confirmed FGF-2 activation of the intrinsic and extrinsic apoptotic pathways and blockade of IGF anti-apoptotic signaling. FGF-2, directly and indirectly, overcomes the proliferative and anti-apoptotic activity of IGF-I by complex mechanisms, including enhancement of differentiation and apoptotic pathways, and inhibition of IGF-I induced anti-apoptotic signalling. Modulation of IGF binding protein abundance by FGF-2 does not play a significant role in inhibition of IGF-I induced mitogenesis.

Gene profile analysis implicates Klotho as an important contributor to aging changes in brain white matter of the rhesus monkey

“…Epidermal growth factor (EGF) and fibroblast growth factor 1 (FGF1) increases were directly shown, as was the decrease of fibroblast growth factor 2 (FGF2). Several studies suggest that the downregulation of FGF2 may enhance remyelination of white matter by FGF1 and neuroprotection by IGF-1 (Armstrong et al, 2002;Diemel et al, 2003;Russo et al, 2004). EGF promotes in vitro proliferation of neuroglia, astrocytes and oligodendrocytes, and is important for proliferation of progenitor cells in the aged brain (Alonso, 1999;Benoit et al, 2001).…”

IGFBP-6 five years on; not so ‘forgotten’?

“…Overexpression of the N-myc oncogene, which is associated with poor prognosis in neuroblastoma, decreased IGFBP-6 and increased IGFBP-2 and IGF-I receptor levels [13]. FGF-2, which stimulates neuronal differentiation, increased IGFBP-6 level in neuroblastoma cells [14].…”

Induction of Id-1 by FGF-2 involves activity of EGR-1 and sensitizes neuroblastoma cells to cell death

“…Inhibition of cellular growth by FGF-2 has been demonstrated in peripheral primitive neuroectodermal tumor-derived SK-N-MC cells, in which it causes a delay in cell cycle progression through the G 2 phase arrest (Smits et al, 2000). In the same cell line FGF-2 can also induce differentiation and apoptosis (Kim et al, 2004; Russo et al, 2004; Ma et al, 2008). …”