Vitamin D Metabolites Activate the Sphingomyelin Pathway and Induce Death of Glioblastoma Cells

Abstract

1 alpha, 25-dihydroxyvitamin D3 was previously shown to induce cell death in brain tumour cell lines when added to the medium at micromolar concentration. In this paper we show that Cholecalciferol, a poor ligand of the vitamin D receptor, also induces cell death of HU197 human glioblastoma cell line and early passages cultures derived from a recurrent human glioblastoma. This finding suggests that the effects of vitamin D metabolites on brain tumour cells are at least partially 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 ceramide and ganglioside GD3 in Hu197 cells after treatment with cholecalciferol. A significant increase in ceramide concentration and a proportional decrease in sphingomyelin was already present after 6 hours of cholecalciferol treatment when no morphological changes were visible in the cultures. Treatment with ceramides (N-acetylsphingosine or natural ceramide from bovine brain) of the same cells also induces cell death. Similarly, treatment of the same cells with bacterial Sphingomyelinase also results in cell death. The demonstration of an increase in intracellular ceramide after cholecalciferol treatment and the ability of ceramide to induce cell death suggest that the sphingomyelin pathway may be implicated in the effect of vitamin D metabolites on human glioblastoma cells. Inhibition of ceramide biosynthesis by fumonisin B1 treatment did not alter the dose response curve of HU197 cells to cholecalciferol. Insensitivity to fumonisin B1 together with a decrease in sphingomyelin content after cholecalciferol treatment indicate that activation of sphingomyelinase should be responsible for the increase in intracellular ceramide concentration.

Low Ultraviolet B and Increased Risk of Brain Cancer: An Ecological Study of 175 Countries

“…UVB irradiance varies inversely with latitude [27] , and photosynthesis in the skin resulting from it is the source of approximately 95% of circulating vitamin D and its metabolites in humans [28] . Previous studies have shown that 25(OH)D [14] and its precursor, vitamin D 3 [15] , can inhibit growth or destroy human glioblastoma cells in vitro.…”

“…These adhesion proteins can be degraded by ionizing radiation, the principal known risk factor for brain cancer. In addition, vitamin D 3 (cholecalciferol) has been shown to induce death of human glioblastoma cells in vitro [14] and another study found that 25(OH)D can cause a significant reduction in growth of glioblastoma cells in vitro [15] .…”

Vitamin D–induced up–regulation of tumour necrosis factor alpha (TNF–α) in prostate cancer cells

“…1a,25-dihydroxyvitamin D 3 (1a,25(OH) 2 D 3 or calcitriol), the hormonally active form of vitamin D is not only a regulator of calcium and phosphate homeostasis but also an effective modulator of cellular proliferation and differentiation in a number of different cell types, including breast, colon and prostate cancer as well as melanoma, myeloma and gliablastoma cells (James et al, 1996;Magrassi et al, 1998;Blutt et al, 2000), for a review see Tuohimaa et al, 2001;Ylikomi et al, 2002).…”

Lack of Sunlight Exposure Influence on Primary Glioblastoma Survival

“…When evaluated in vitro studies planned to explain the relationship between vitamin D and GBM, generally their results shown vitamin D and its metabolites induce death of GBM cell lines (Naveilhan et al, 1994;Baudet et al, 1996;Magrassi et al, 1998). One of the effects of sunlight exposure on cancer prognosis may be mediated by vitamin D and its metabolites.…”