Effects of the histone deacetylase inhibitor valproic acid on Notch signalling in human neuroblastoma cells.
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.
Stockhausen
M-T
MT
Department of Laboratory Medicine, Division of Molecular Medicine, Lund University, University Hospital MAS, S-205 02 Malmö, Sweden.
Sjölund
J
J
Manetopoulos
C
C
Axelson
H
H
D000927:Anticonvulsants / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins; D015152:Blotting, Northern; D015153:Blotting, Western; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000138:chemical synthesis; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors; D018398:Homeodomain Proteins / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008156:Luciferases / Q000032:analysis; D008565:Membrane Proteins / Q000187:drug effects* / Q000378:metabolism*; D009447:Neuroblastoma / Q000201:enzymology / Q000378:metabolism*; D010641:Phenotype; D012334:RNA, Neoplasm / Q000302:isolation & purification; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism; D051880:Receptors, Notch; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D000072056:Transcription Factor HES-1; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*
D000927:Anticonvulsants; D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D018398:Homeodomain Proteins; D008156:Luciferases; D008565:Membrane Proteins; D012334:RNA, Neoplasm; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; D014635:Valproic Acid; C065500:ASCL1 protein, human; C497761:NOTCH1 protein, human; C078493:HES1 protein, human