Valproic acid upregulates the expression of the p75NTR/sortilin receptor complex to induce neuronal apoptosis
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Valproic acid upregulates the expression of the p75NTR/sortilin receptor complex to induce neuronal apoptosis Simona Dedoni1 · Luisa Marras2 · Maria C. Olianas1 · Angela Ingianni2 · Pierluigi Onali1
© The Author(s) 2020
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. Keywords Histone deacetylase inhibitors · p75NTR · Sortilin · Human neuroblastoma cells · Mouse cerebellar granule cells · Apoptosis
Introduction Valproic acid (VPA) is a short-chain branched fatty acid widely used for its anticonvulsant, mood-stabilizing and analgesic properties [1, 2], More recently, clinical trials have shown that VPA displays anti-cancer activity in different Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10495-020-01626-0) contains supplementary material, which is available to authorized users. * Pierluigi Onali [email protected] 1
Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, CA, Italy
Section of Microbiology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
2
types of tumours [3, 4]. The anticonvulsant and mood stabilizing effects have been classically attributed to VPA blockade of sodium and calcium channels, potentiation of inhibitory neurotransmission and modulati
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