New signalling pathway involved in the anti-proliferative action of vitamin D3 and its analogues in human neuroblastoma cells. A role for ceramide kinase

摘要: Abstract 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), a crucial regulator of calcium/phosphorus homeostasis, has important physiological effects on growth and differentiation in variety malignant non-malignant cells. Synthetic structural hormone analogues, with lower hypercalcemic side effects, are currently under clinical investigation. Sphingolipids appear to be bioactive factors the control cell fate: phosphorylated forms, sphingosine-1-phosphate (S1P) ceramide-1-phosphate (C1P), mitogenic factors, whereas sphingosine ceramide (Cer) usually act as pro-apoptotic agents. Although many studies correlate S1P function impaired growth, relevance C1P/Cer system its involvement neuroblastoma cells remain clarified. Here, we demonstrated anti-proliferative effect 1,25(OH)2D3 well ZK156979 ZK191784, human SH-SY5Y cells, judged by [3H]thymidine incorporation, evaluation active ERK1/2 levels. The inhibition kinase (CerK), enzyme responsible for C1P synthesis, specific gene silencing or pharmacological inhibition, drastically reduced proliferation. ZK191784 treatment induced significant decrease CerK expression content, an increase Cer. Notably, ZK159222, antagonist receptor, trichostatin A, inhibitor histone deacetylases, COUP-TFI-siRNA prevented elicited supporting VDR/COUP-TFI/histone deacetylase complex regulation. Altogether, these findings provide first evidence that CerK/C1P axis acts molecular effector action thereby representing new possible target anti-cancer therapy neuroblastoma.