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Glucocorticoids inhibit apoptosis during fibrosarcoma development by transcriptionally activating Bcl-xL
Duncan M Gascoyne1, Robert M Kypta, Maria d M Vivanco
1Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, United Kingdom.
Abstract:
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.
Insights
Glucocorticoids, like dexamethasone, repress fibrosarcoma cell apoptosis by inducing the Bcl-x(L) protein. This key protein mediates the anti-apoptotic effects of glucocorticoids during tumor development.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Glucocorticoids modulate diverse physiological processes, including apoptosis.
- Apoptosis increases during fibrosarcoma development, but its regulation by glucocorticoids is cell-type dependent.
Purpose of the Study:
- To investigate the molecular mechanisms by which glucocorticoids regulate apoptosis during fibrosarcoma development.
- To identify key molecular targets mediating the anti-apoptotic effects of glucocorticoids in fibrosarcoma.
Main Methods:
- Analysis of apoptosis levels in fibrosarcoma cells.
- Dexamethasone treatment and assessment of Bcl-x(L) protein expression.
- Transcriptional activation assays using the Bcl-x promoter.
- Chromatin immunoprecipitation (ChIP) to assess glucocorticoid receptor (GR) binding.
- Inhibition of apoptosis using exogenous Bcl-x(L).
Main Results:
- Dexamethasone repressed apoptosis in fibrosarcoma cells.
- Bcl-x(L) protein expression was induced by dexamethasone at the transcriptional level.
- The ligand-activated glucocorticoid receptor (GR) directly activated the Bcl-x promoter.
- GR binding to the Bcl-x promoter was confirmed in vitro and in vivo.
- Exogenous Bcl-x(L) mimicked the anti-apoptotic effects of dexamethasone.
Conclusions:
- Bcl-x(L) is a critical molecular target mediating the anti-apoptotic effects of glucocorticoids in fibrosarcoma.
- Glucocorticoid receptor-mediated induction of Bcl-x(L) plays a significant role in regulating cell death during fibrosarcoma tumorigenesis.