Glucocorticoids inhibit apoptosis during fibrosarcoma development by transcriptionally activating Bcl-xL.
Glucocorticoids influence many physiological processes, and in particular apoptosis, often with opposite effects depending on the cell type examined. We found that during fibrosarcoma development there is a strong increase in apoptosis at the tumor stage, which is repressed by dexamethasone to levels observed in normal fibroblasts. The anti-apoptotic Bcl-2 family protein Bcl-x(L) is induced by dexamethasone at the transcriptional level at all stages of fibrosarcoma development. The ligand-activated glucocorticoid receptor (GR) activates the Bcl-x promoter in transient transfection experiments, and GR binds to specific Bcl-x promoter sequences in vitro and in vivo. Furthermore, a GR antagonist abolishes this effect, indicating that Bcl-x(L) induction is mediated by GR. Importantly, exogenous Bcl-x(L) inhibits apoptosis and caspase-3 activity in fibrosarcoma cells to levels found in dexamethasone-treated fibrosarcoma cells. We conclude that Bcl-x(L) is a key target mediating the anti-apoptotic effects of glucocorticoids during fibrosarcoma development. These observations provide further understanding of the molecular basis of glucocorticoid regulation of cell death during tumorigenesis.
Gascoyne
Duncan M
DM
Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, United Kingdom.
Kypta
Robert M
RM
Vivanco
Maria d M
Md
D017209:Apoptosis; D015152:Blotting, Northern; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D018450:Disease Progression; D005354:Fibrosarcoma / Q000378:metabolism* / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D008957:Models, Genetic; D009369:Neoplasms / Q000473:pathology; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D002843:Chromatin; D005938:Glucocorticoids; D019253:Proto-Oncogene Proteins c-bcl-2; D011965:Receptors, Glucocorticoid; D051020:bcl-X Protein; D003907:Dexamethasone; D004247:DNA; D020169:Caspases