Vitamin D receptor stable transfection restores the susceptibility to 1,25-dihydroxyvitamin D3 cytotoxicity in a rat glioma resistant clone.
Recently, 1,25-dihydroxyvitamin D3 (1,25-D3) and less hypercalcemic analogs were shown to exert a delayed cytotoxic effect on rat C6 glioma cells. 1,25-D3 induces in these cells a programmed cell death, accompanied by the induction of c-myc, p53 and gadd 45 genes. The involvement of the intracellular vitamin D receptor (VDR) remained to be determined. In this lethal process, we have investigated its role in a subclone of C6 cells, which was isolated on the basis of its resistance to 1,25-D3, and in which VDR expression was not detected either at the mRNA or protein levels. The stable transfection of a rat VDR cDNA into this clone restored its susceptibility to the cytotoxic effects of 1,25-D3. This phenomenon was accompanied by a dramatic upregulation of c-myc mRNA expression, as already described in a C6-sensitive clone. These results provide the first evidence that VDR expression, if not sufficient, is necessary to mediate 1,25-D3 cytotoxic effect in C6 glioma cells. Since VDR mRNA expression has been already reported in human brain tumors, our data imply that the identification of VDR expression could become a prerequisite in any strategy of glioma treatment with vitamin D analogs.
Davoust
N
N
Institut National de la Santé et de la Recherche Médicale, Centre Hospitalier Universitaire, Angers, France.
Wion
D
D
Chevalier
G
G
Garabedian
M
M
Brachet
P
P
Couez
D
D
D000818:Animals; D002117:Calcitriol / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002999:Clone Cells; D053938:DNA Fragmentation / Q000187:drug effects; D018076:DNA, Complementary / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D016259:Genes, myc / Q000187:drug effects; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D051381:Rats; D018167:Receptors, Calcitriol / Q000096:biosynthesis / Q000235:genetics*; D014162:Transfection / Q000187:drug effects*
D018076:DNA, Complementary; D018167:Receptors, Calcitriol; D002117:Calcitriol