Document Detail

New signalling pathway involved in the antiproliferative action of vitamin D(3) and its analogues in human neuroblastoma cells. A role for ceramide kinase.
MedLine Citation:
PMID:  22579669     Owner:  NLM     Status:  Publisher    
1α,25-dihydroxyvitamin D3 (1,25(OH)(2)D(3)), 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)(2)D(3) as well as of its structural analogues, ZK156979 and ZK191784, in human SH-SY5Y cells, as judged by [(3)H]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)(2)D(3) 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)(2)D(3) receptor, trichostatin A, inhibitor of histone deacetylases, and COUP-TFI-siRNA prevented the decrease of CerK expression elicited by 1,25(OH)(2)D(3) 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)(2)D(3) and its analogues, thereby representing a new possible target for anti-cancer therapy of human neuroblastoma.
Francesca Bini; A Alessia Frati; Mercedes Garcia-Gil; Chiara Battistini; Maria Granado; Maria Martinesi; Marco Mainardi; Eleonora Vannini; Federico Luzzati; Matteo Caleo; Paolo Peretto; Antonio Gomez-Muñoz; Elisabetta Meacci
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-5-8
Journal Detail:
Title:  Neuropharmacology     Volume:  -     ISSN:  1873-7064     ISO Abbreviation:  -     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-5-14     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0236217     Medline TA:  Neuropharmacology     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 Elsevier Ltd. All rights reserved.
Department of Biochemical Sciences, University of Florence (Italy).
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