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Published on: March 12, 2019
Glucocorticoid effects on growth, and androgen receptor concentrations in DDT1MF-2 cell lines
Abstract:
The DDT1MF-2 smooth muscle tumor cell line contains receptors for and is differentially sensitive to androgens and glucocorticoids. Androgens stimulate and glucocorticoids inhibit growth. We now confirm that the latter involves the induction of a block in the G1 phase of the cell cycle. We have developed and characterized in vitro and in vivo a glucocorticoid resistant variant of this cell line, the DDT1MF-2-GR. Glucocorticoids specifically inhibit androgen induced androgen receptor augmentation in DDT1MF-2 cells, but not in the GR variant suggesting that growth inhibition is related to inhibition of androgen receptor augmentation. However, under optimal conditions for cell proliferation, when glucocorticoid inhibited growth is relieved by the exogenous addition of platelet derived growth factor, androgen receptor augmentation is still suppressed. Thus, androgen induced elevation in androgen receptor concentrations is not a prerequisite for cell proliferation. These results imply that in androgen responsive cells, although androgen stimulation of growth can be blocked by antagonism of androgen receptor mediated events, the antagonism can be bypassed by supplying the cells with exogenous growth factors. These results provoke speculation on how cells, which are dependent upon androgens for growth, become autonomous.
Insights
Glucocorticoids inhibit smooth muscle tumor cell growth by blocking the cell cycle. This inhibition can be bypassed by external growth factors, even when androgen receptor augmentation is suppressed.
Area of Science:
- Endocrinology
- Cell Biology
- Cancer Research
Background:
- DDT1MF-2 smooth muscle tumor cells exhibit differential sensitivity to androgens and glucocorticoids.
- Androgens stimulate, while glucocorticoids inhibit, cell growth, with glucocorticoids inducing a G1 cell cycle block.
Purpose of the Study:
- To investigate the mechanism of glucocorticoid-induced growth inhibition in DDT1MF-2 cells.
- To characterize a glucocorticoid-resistant variant (DDT1MF-2-GR) and its implications for androgen receptor regulation and cell proliferation.
Main Methods:
- Development and characterization of a glucocorticoid-resistant cell line (DDT1MF-2-GR).
- Assessment of cell cycle progression and androgen receptor augmentation under various hormonal and growth factor conditions.
Main Results:
- Glucocorticoids inhibit androgen-induced androgen receptor augmentation in sensitive cells, but not in the resistant variant.
- Exogenous platelet-derived growth factor can overcome glucocorticoid-mediated growth inhibition, independent of androgen receptor augmentation.
- Androgen receptor augmentation is not essential for cell proliferation under all conditions.
Conclusions:
- Glucocorticoid-induced growth inhibition in androgen-responsive cells involves antagonism of androgen receptor-mediated events.
- Exogenous growth factors can bypass androgen receptor-dependent pathways, suggesting a mechanism for acquired autonomy in hormone-dependent cancers.
- Cellular proliferation can be sustained through alternative signaling pathways, even when hormone-dependent growth mechanisms are blocked.
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