| New signalling pathway involved in the antiproliferative action of vitamin D(3) and its analogues in human neuroblastoma cells. A role for ceramide kinase. | |
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MedLine Citation:
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PMID: 22579669 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: JOURNAL ARTICLE Date: 2012-5-8 |
Journal Detail:
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Title: Neuropharmacology Volume: - ISSN: 1873-7064 ISO Abbreviation: - Publication Date: 2012 May |
Date Detail:
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Created Date: 2012-5-14 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0236217 Medline TA: Neuropharmacology Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2012 Elsevier Ltd. All rights reserved. |
Affiliation:
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Department of Biochemical Sciences, University of Florence (Italy). |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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