1,25-Dihydroxyvitamin D3 induces programmed cell death in a rat glioma cell line.
1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), a seco-steroid hormone with potential antitumoral activities, has been recently reported to exert cytotoxic effects on C6 glioma cells. However, the molecular mechanisms which trigger this cell death remain unknown. We show here that this 1,25(OH)2D3-induced cell death is dependent upon protein synthesis and is accompanied by the expression of c-myc, p53, and gadd45 genes. Two other genes, coding for interleukin-6 and vaso-endothelial growth factor, are also upregulated after addition of 1,25(OH)2D3. This programmed cell death can be suppressed when cells are treated with 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)2D3-treated 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 1,25(OH)2D3 in glioma cells and may provide a basis for the development of new therapeutic strategies. In addition, these data also suggest that the treatment of C6.9 cells with 1,25(OH)2D3 may be a useful model to study the molecular mechanisms involved in the programmed cell death of a cell of glial origin.
Baudet
C
C
INSERM U 298, Centre Hospitalier Universitaire, Angers, France.
Chevalier
G
G
Chassevent
A
A
Canova
C
C
Filmon
R
R
Larra
F
F
Brachet
P
P
Wion
D
D
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002117:Calcitriol / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics; D019833:Genistein; D005910:Glioma / Q000473:pathology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D007529:Isoflavones / Q000494:pharmacology; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000097642:GADD45 Proteins
D002117:Calcitriol; D005576:Colforsin; D003513:Cycloheximide; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D019833:Genistein; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D007529:Isoflavones; D008222:Lymphokines; D009419:Nerve Tissue Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000097642:GADD45 Proteins; C539820:Nr4a1 protein, rat