Progetto IBERNAT-NBL_ articolo: Valproic acid upregulates the expression of the p75NTR/sortilin receptor complex to induce neuronal apoptosis
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Data
2020-10-25
Autori
ONALI, PIERLUIGI
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Abstract
The antiepileptic and mood stabilizer agent valproic acid (VPA) has been shown to exert anti-tumour effects and to cause
neuronal damage in the developing brain through mechanisms not completely understood. In the present study we show that
prolonged exposure of SH-SY5Y and LAN-1 human neuroblastoma cells to clinically relevant concentrations of VPA caused
a marked induction of the protein and transcript levels of the common neurotrophin receptor p75NTR and its co-receptor
sortilin, two promoters of apoptotic cell death in response to proneurotrophins. VPA induction of p75NTR and sortilin was
associated with an increase in plasma membrane expression of the receptor proteins and was mimicked by cell treatment with
several histone deacetylase (HDAC) inhibitors. VPA and HDAC1 knockdown decreased the level of EZH2, a core component
of the polycomb repressive complex 2, and upregulated the transcription factor CASZ1, a positive regulator of p75NTR.
CASZ1 knockdown attenuated VPA-induced p75NTR overexpression. Cell treatment with VPA favoured proNGF-induced
p75NTR/sortilin interaction and the exposure to proNGF enhanced JNK activation and apoptotic cell death elicited by VPA.
Depletion of p75NTR or addition of the sortilin agonist neurotensin to block proNGF/sortilin interaction reduced the apoptotic
response to VPA and proNGF. Exposure of mouse cerebellar granule cells to VPA upregulated p75NTR and sortilin
and induced apoptosis which was enhanced by proNGF. These results indicate that VPA upregulates p75NTR apoptotic cell
signalling through an epigenetic mechanism involving HDAC inhibition and suggest that this effect may contribute to the
anti-neuroblastoma and neurotoxic effects of VPA.
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Keywords
Valproic Acid, p75NTR, sortilin, Human neuroblastoma cells