Effects of the histone deacetylase inhibitor valproic acid on Notch signalling in human neuroblastoma cells

Abstract

Neuroblastoma (NB), a sympathetically derived childhood tumour, shows characteristics of neuronal precursor cells, suggesting a halted differentiation process. We have previously shown that the Notch signalling cascade, a key player during normal neurogenesis, also might be involved in NB differentiation. Valproic acid (VPA), a well-tolerated antiepileptic drug, has been shown to induce differentiation and cell death of NB cells, possibly associated with its recently described HDAC inhibiting activity. Stimulation of NB cells with VPA led to increased cell death and phenotypic changes associated with differentiation, that is, neurite extension and upregulation of neuronal markers. VPA treatment also led to an activated Notch signalling cascade as shown by increased levels of intracellular Notch-1 and Hes-1, mimicking the initial phase of induced differentiation. These results reinforce that VPA potentially could be used in differentiation therapy of NB and that the effects in part could be a consequence of interference with the Notch signalling cascade.

Down-modulation of SEL1L, an Unfolded Protein Response and Endoplasmic Reticulum-associated Degradation Protein, Sensitizes Glioma Stem Cells to the Cytotoxic Effect of Valproic Acid

“…It can be speculated that the VPA effect on GSC viability could partially be a consequence of the interference on Notch/Hedgehog cascades, with important implications in glioma therapy. In support to our findings, several reports underlined the mis-regulation of Notch signaling cascade mediated by VPA as a novel strategy for cancer therapy (46,51,52).…”

Acetylation controls Notch3 stability and function in T-cell leukemia

“…However, how acetylation and deacetylation control Notch pathway remains to be clarified. It has been observed that HDACi promote differentiation and cell death of neuroblastoma cells, likely due to suppression of Notch signaling (Stockhausen et al, 2005).…”

Valproic Acid Induces Notch1 Signaling in Small Cell Lung Cancer Cells

“…VPA has been shown to inhibit growth in several tumor cell lines (13,19,20,24). To date, the effect of VPA treatment on SCLC cell growth has not been characterized.…”

“…We have previously shown that Notch1 signaling is minimal or absent at baseline in several NET cell lines, and that expression of exogenous Notch1 via an inducible construct inhibits NET cell growth (6,14). Additionally, VPA has been reported to activate Notch1 signaling in neuroblastoma, carcinoid, and medullary thyroid cancer cells (13,19,20). We hypothesized, then, that VPA may also activate Notch1 signaling in SCLC cells with subsequent anti-tumor effects.…”