Abstract
Simple SummaryThe active form of vitamin D3 slows proliferation and stimulates differentiation of glioblastoma cells with mutated p53 by acting via neutral sphingomyelinase 1 and not by classical via vitamin D receptor-mediatedGlioblastoma is one the most aggressive primary brain tumors in adults, and, despite the fact that radiation and chemotherapy after surgical approaches have been the treatments increasing the survival rates, the prognosis of patients remains poor. Today, the attention is focused on highlighting complementary treatments that can be helpful in improving the classic therapeutic approaches. It is known that 1α,25(OH)2 vitamin D3, a molecule involved in bone metabolism, has many serendipidy effects in cells. It targets normal and cancer cells via genomic pathway by vitamin D3 receptor or via non-genomic pathways. To interrogate possible functions of 1α,25(OH)2 vitamin D3 in multiforme glioblastoma, we used three cell lines, wild-type p53 GL15 and mutant p53 U251 and LN18 cells. We demonstrated that 1α,25(OH)2 vitamin D3 acts via vitamin D receptor in GL15 cells and via neutral sphingomyelinase1, with an enrichment of ceramide pool, in U251 and LN18 cells. Changes in sphingomyelin/ceramide content were considered to be possibly responsible for the differentiating and antiproliferative effect of 1α,25(OH)2 vitamin D in U251 and LN18 cells, as shown, respectively, in vitro by immunofluorescence and in vivo by experiments of xenotransplantation in eggs. This is the first time 1α,25(OH)2 vitamin D3 is interrogated for the response of multiforme glioblastoma cells in dependence on the p53 mutation, and the results define neutral sphingomyelinase1 as a signaling effector.
Highlights
Glioblastoma multiforme (GBM) is the most common and one of the most aggressive primary intracerebral tumors with great heterogeneity in tissue histology and imaging [1]
D3 or cholecalciferol is first hydroxylated in carbon 25 in the liver to form 25(OH) vitamin D3 or calcidiol and it is hydroxylated in carbon 1 in the kidney to form 1α,25(OH)2 VD3
The relevance of SM breakdown in cancer cell fate underscored by the role of acid sphingomyelinase (aSMase) in modulation and of neutral SMase (nSMase) in cell differentiation modulation [18,26,28] became a determinant for us to apoptosis modulation and of nSMase in cell differentiation modulation [18,26,28] became a investigate its behavior in GBM cells treated with 1α,25(OH)2 VD3
Summary
Glioblastoma multiforme (GBM) is the most common and one of the most aggressive primary intracerebral tumors with great heterogeneity in tissue histology and imaging [1]. As early as 1995 Magrassi et al [7] had demonstrated that activated 1α,25(OH) vitamin D3 or calcitriol (1α,25(OH) VD3) was capable of inducing a significant (>50%) reduction in growth of glioblastoma cells at dosages over 5 μM. D3 or cholecalciferol is first hydroxylated in carbon 25 in the liver to form 25(OH) vitamin D3 or calcidiol and it is hydroxylated in carbon 1 in the kidney to form 1α,25(OH) VD3. Glioblastoma was able to metabolize cholecalciferol to calcidiol [8]. It has been demonstrated that five cell lines of GBM, asTx3095, Tx3868, U87, U118, U373, were resistant against the antiproliferative activity of 1α,25(OH) VD3 at the dosage of 10−6 , 10−8 , and 10−10 M [9].
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