1,25-DIHYDROXYVITAMIN-D3 INDUCES PROGRAMMED CELL-DEATH IN A RAT GLIOMA CELL-LINE

1,25-Dihydroxyvitamin D3 (1,25(OH)(2)D-3), a seco-steroid hormone with potential antitumoral activities, has been recently reporterd to exer t cytotoxic effects on C6 glioma cells. However, the molecular mechani sms which trigger this cell death remain unknown. We show here that th is 1,25(OH)(2)D-3-induced cell death is dependent upon protein synthes is and is accompanied by the expression off c-myc, p53, and gadd45 gen es, Two other genes, coding for interleukin-6 and vaso-endothelial gro wth factor, dare also up-regulated after addition of 1,25(OH)(2)D-3, T his programmed cell death can be suppressed when cells are treated wit h forskolin, a drug which increases intracellular cAMP concentration, or with genistein, an inhibitor of tyrosine protein kinases. However, in spite of the demonstration of fragmented DNA in 1,25(OH)(2)D-3-trea ted cells, the C6.9 cells used in this study do not show the classical morphological features of apoptosis, These results provide the first evidence for the existence of a programmed cell death triggered by 1,2 5(OH)(2)D-3 in glioma cells and may provide a basis for the developmen t off new therapeutic strategies, In addition, these data also suggest that the treatment of C6.9 cells with 1,25(OH)(2)D-3 may be a useful model to study the molecular mechanisms involved inn the programmed ce ll death of a cell of glial origin. (C) 1996 Wiley-Liss, Inc.