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.
Highlights
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 differentElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Exposure to VPA has been reported to exert either neuroprotective or neurotoxic effects
Western blot analysis showed that prolonged exposure (24 h) of either SH-SY5Y or LAN-1 cells to VPA (1 mM) induced a marked increase in the expression of p75NTR immunoreactivity, which comprised a major band of 75 kDa and a faster migrating band likely corresponding to a lower glycosylation state of the receptor [36] (Fig. 1a and d)
Real-time qRT-PCR analysis indicated that VPA (1 mM) significantly enhanced the steady state levels of p75NTR and sortilin mRNAs in both SHSY5Y and LAN-1 cells (Fig. 1c and f)
Summary
Exposure to VPA has been reported to exert either neuroprotective or neurotoxic effects. There is strong evidence that VPA can adversely affect neural growth and survival, and induce. Prenatal exposure to VPA has been associated with neurodevelopmental defects and increased risk of autism spectrum disorder and childhood autism in the offspring [17, 18] a number of studies have demonstrated that VPA inhibits the growth and induces cell death of human neuroblastoma cells [19,20,21,22]. Other studies have shown that the exposure to VPA promotes the proliferation and survival of neuroblastoma cells [23, 24]
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