OBJECTIVE: The neurotrophin nerve growth factor (NGF) affects survival, regulation and differentiation of both central and peripheral nervous system neurons. NGF exerts its effects primarily through tropomyosin receptor kinase A (TrkA), inducing a cascade of tyrosine kinase-initiated responses. In spite of its importance, the general behavior of NGF looks contradictory: its effects can be both stimulatory and inhibitory. The present study aims to explore the molecular mechanisms induced by NGF in glioma cancer cells. METHODS: The effects of NGF were investigated in high grade glioma and low grade pediatric glioma (PLGG) cell lines through comparative studies. In particular, we investigated TrkA-mediated cellular pathways, molecular signaling, proliferation, cell cycle and cellular senescence. RESULTS: We found that exposure of PLGG cells to NGF produced stable growth arrest with the features of a senescence phenotype but without the expression of anti-poly(ADP-ribose) polymerase cleavage, a marker of apoptosis. Moreover, NGF treatment promoted the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2), signal transducer and activator of transcription 3 (STAT3), and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling. In addition, K252a, a TrkA inhibitor, significantly reduced the phosphorylation of the aforementioned signaling pathways, suggesting that NGF-activated ERK1/2 and AKT signaling take place downstream of TrkA-neurotrophin interaction. CONCLUSIONS: These findings provide the first evidence that NGF can induce senescence of PLGG cells in a receptor-mediated fashion, thus supporting the hypothesis that in the clinical setting NGF might be beneficial to pediatric glioma patients.

Meco, D., Di Francesco, A. M., Melotti, L., Ruggiero, A., Riccardi, R., Ectopic nerve growth factor prevents proliferation in glioma cells by senescence induction, <<JOURNAL OF CELLULAR PHYSIOLOGY>>, 2019; 234 (5): 6820-6830. [doi:10.1002/jcp.27430] [http://hdl.handle.net/10807/148168]

Ectopic nerve growth factor prevents proliferation in glioma cells by senescence induction

Meco, Daniela
Primo
;
Melotti, Linda;Ruggiero, Antonio;Riccardi, Riccardo
Ultimo
2019

Abstract

OBJECTIVE: The neurotrophin nerve growth factor (NGF) affects survival, regulation and differentiation of both central and peripheral nervous system neurons. NGF exerts its effects primarily through tropomyosin receptor kinase A (TrkA), inducing a cascade of tyrosine kinase-initiated responses. In spite of its importance, the general behavior of NGF looks contradictory: its effects can be both stimulatory and inhibitory. The present study aims to explore the molecular mechanisms induced by NGF in glioma cancer cells. METHODS: The effects of NGF were investigated in high grade glioma and low grade pediatric glioma (PLGG) cell lines through comparative studies. In particular, we investigated TrkA-mediated cellular pathways, molecular signaling, proliferation, cell cycle and cellular senescence. RESULTS: We found that exposure of PLGG cells to NGF produced stable growth arrest with the features of a senescence phenotype but without the expression of anti-poly(ADP-ribose) polymerase cleavage, a marker of apoptosis. Moreover, NGF treatment promoted the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2), signal transducer and activator of transcription 3 (STAT3), and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling. In addition, K252a, a TrkA inhibitor, significantly reduced the phosphorylation of the aforementioned signaling pathways, suggesting that NGF-activated ERK1/2 and AKT signaling take place downstream of TrkA-neurotrophin interaction. CONCLUSIONS: These findings provide the first evidence that NGF can induce senescence of PLGG cells in a receptor-mediated fashion, thus supporting the hypothesis that in the clinical setting NGF might be beneficial to pediatric glioma patients.
Inglese
Meco, D., Di Francesco, A. M., Melotti, L., Ruggiero, A., Riccardi, R., Ectopic nerve growth factor prevents proliferation in glioma cells by senescence induction, <<JOURNAL OF CELLULAR PHYSIOLOGY>>, 2019; 234 (5): 6820-6830. [doi:10.1002/jcp.27430] [http://hdl.handle.net/10807/148168]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10807/148168
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