30. Vitamin D metabolites activate the sphingomyelin pathway and induce cell death of glioblastoma cells in vitro

L. Magrassi, L. Adorni, G. Montorfano, S. Rapelli, G. Butti, B. Berra, G. Milanesi

Research output: Contribution to journalArticle

Abstract

Cholecalciferol (vit. D3) rapidly induces cell death of brain tumor cell lines when added to the medium at micromolar concentrations. Cholecalciferol is a poor ligand of the vitamin D receptor and its metabolic conversion to 1,25-dihydroxycholecalciferol requires two hydroxilation steps. This suggests that its effect is independent from the activation of the classic nuclear receptor pathway. Vitamin D metabolites have been shown to activate the sphingomyelin pathway inducing an increase in cellular ceramide concentration. We determined the levels of sphingomyelin and ceramide in Hu197 a human glioblastoma cell line after treatment with cholecalciferol. A significant increase in ceramide concentration and a proportional decrease in sphingomyelin was already present after 6 hours of vit. D3 treatment when no morphological changes are visible in the cultures. Treatment with ceramides of HU197 cells or glioblastoma primary cultures induces cell death. Similarly, treatment of the same cells with bacterial Sphingomyelinase also results in cell death. The ability of ceramide to induce cell death and the demonstration of an increase in intracellular ceramide after cholecalciferol treatment show that the apoptotic pathway down-stream of ceramide release is functional and suggest that the sphingomyelin pathway may be implicated in the effects of vitamin D metabolites on glioblastoma cells. Inhibition of ceramide biosynthesis by fumonisin B1 treatment did not alter the dose response curve of HU197 cells to cholecalciferol treatment. Insensitivity to fumonisin B1 together with a decrease in sphingomyelin content after cholecalciferol treatment indicate that activation of sphingomyelinases should be responsible for the increase in intracellular ceramide concentration.

Original languageEnglish
Pages (from-to)249-250
Number of pages2
JournalItalian Journal of Neurological Sciences
Volume18
Issue number4
Publication statusPublished - 1997

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology

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