VITAMIN-D-RECEPTOR STABLE TRANSFECTION RESTORES THE SUSCEPTIBILITY TO1,25-DIHYDROXYVITAMIN D-3 CYTOTOXICITY IN A RAT GLIOMA RESISTANT CLONE

Recently, 1,25-dihydroxyvitamin D-3 (1,25-D-3) and less hypercalcemic analogs were shown to exert a delayed cytotoxic effect on rat C6 gliom a cells. 1,25-D-3 induces in these cells a programmed cell death, acco mpanied by the induction of c-myc, p53 and gadd 45 genes. The involvem ent of the intracellular vitamin D receptor (VDR) remained to be deter mined. In this lethal process, we have investigated its role in a subc lone 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 m RNA or protein levels. The stable transfection of a rat VDR cDNA into this clone restored its susceptibility to the cytotoxic effects of 1,2 5-D-3, This phenomenon was accompanied by a dramatic upregulation of c -myc mRNA expression, as already described in a C6-sensitive clone. Th ese results provide the first evidence that VDR expression, if not suf ficient, is necessary to mediate 1,25-D-3 cytotoxic effect in C6 gliom a 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. (C) 1998 Wiley-Liss, Inc.