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

Marco Mainardi, F Bini, A Frati, M Garcia Gil, C Battistini, M Granado, M Martinesi, E Vannini, F Luzzati, M Caleo, P Peretto, A Gomez Muñoz, E. Meacci

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

30 Citazioni (Scopus)

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 a variety of malignant and non-malignant cells. Synthetic structural hormone analogues, with lower hypercalcemic side effects, are currently under clinical investigation. Sphingolipids appear to be crucial bioactive factors in the control of the cell fate: the phosphorylated forms, sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P), are mitogenic factors, whereas sphingosine and ceramide (Cer) usually act as pro-apoptotic agents. Although many studies correlate S1P function to impaired cell growth, the relevance of C1P/Cer system and its involvement in neuroblastoma cells remain to be clarified. Here, we demonstrated the anti-proliferative effect of 1,25(OH)₂D₃ as well as of its structural analogues, ZK156979 and ZK191784, in human SH-SY5Y cells, as judged by [³H]thymidine incorporation, cell growth and evaluation of active ERK1/2 levels. The inhibition of ceramide kinase (CerK), the enzyme responsible for C1P synthesis, by specific gene silencing or pharmacological inhibition, drastically reduced cell proliferation. 1,25(OH)₂D₃ and ZK191784 treatment induced a significant decrease in CerK expression and C1P content, and an increase of Cer. Notably, the treatment of SH-SY5Y cells with ZK159222, antagonist of 1,25(OH)₂D₃ receptor, trichostatin A, inhibitor of histone deacetylases, and COUP-TFI-siRNA prevented the decrease of CerK expression elicited by 1,25(OH)₂D₃ supporting the involvement of VDR/COUP-TFI/histone deacetylase complex in CerK regulation. Altogether, these findings provide the first evidence that CerK/C1P axis acts as molecular effector of the anti-proliferative action of 1,25(OH)₂D₃ and its analogues, thereby representing a new possible target for anti-cancer therapy of human neuroblastoma.
Lingua originaleEnglish
pagine (da-a)524-537
Numero di pagine14
RivistaNeuropharmacology
Volume63
DOI
Stato di pubblicazionePubblicato - 2012

Keywords

  • Antineoplastic Agents
  • Calcitriol
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Ceramides
  • Drugs, Investigational
  • Enzyme Inhibitors
  • Gene Silencing
  • Histone Deacetylase Inhibitors
  • Humans
  • Molecular Targeted Therapy
  • Neoplasm Proteins
  • Neuroblastoma
  • Phosphotransferases (Alcohol Group Acceptor)
  • RNA, Small Interfering
  • Receptors, Calcitriol
  • Signal Transduction
  • Vitamin D

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