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Glucocorticoids manifest androgenic activity in a cell line derived from a metastatic prostate cancer
C Y Chang1, P J Walther, D P McDonnell
1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Abstract:
The pathophysiological mechanism(s) by which androgen independence develops in prostate cancer remains to be determined. The identification in many prostate cancer specimens of a mutant androgen receptor, T877A, with altered ligand specificity has provided an explanation for some treatment failures. The T877A mutant androgen receptor recognizes a number of nonandrogenic compounds, including certain estrogens, progestins, and even antiandrogens as androgens. However, a comprehensive screen for hormonal agents which display agonist activity on this mutant has not been performed. In this study, we characterized this clinically important receptor mutant further and found that it can be activated by a wide range of compounds, including a number of endogenous glucocorticoids. Among the most clinically relevant compounds identified are DOC and corticosterone, both of which can effectively activate the mutant receptor at concentrations normally found in blood. Dexamethasone, a synthetic glucocorticoid frequently used in various contexts for prostate cancer therapy, is also recognized as an androgen by the mutant receptor. These unexpected findings suggest the need to: (a) reassess the role of adrenally derived glucocorticoids in prostate cancer disease progression; and (b) recognize the potential for iatrogenic stimulation of disease progression with certain glucocorticoid interventions.
Insights
Prostate cancer can become resistant to treatment due to a mutant androgen receptor (T877A) activated by glucocorticoids. This includes common drugs like dexamethasone, potentially worsening disease progression.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Androgen independence is a key mechanism in prostate cancer progression.
- A mutant androgen receptor (T877A) with altered ligand specificity explains some treatment failures.
- The T877A mutant can be activated by non-androgenic compounds.
Purpose of the Study:
- To further characterize the T877A mutant androgen receptor.
- To identify hormonal agents that activate the T877A mutant.
- To investigate the role of glucocorticoids in activating the T877A mutant.
Main Methods:
- Comprehensive screening of hormonal agents for agonist activity on the T877A mutant.
- Characterization of the T877A mutant's response to various endogenous and synthetic compounds.
- Analysis of activation at physiologically relevant concentrations.
Main Results:
- The T877A mutant androgen receptor is activated by a wide range of compounds.
- Endogenous glucocorticoids like DOC and corticosterone activate the T877A mutant at normal blood concentrations.
- Synthetic glucocorticoids, including dexamethasone, are recognized as androgens by the T877A mutant.
Conclusions:
- Glucocorticoids can activate the T877A mutant androgen receptor, suggesting a role in prostate cancer progression.
- Adrenally derived glucocorticoids warrant reassessment in prostate cancer disease progression.
- Glucocorticoid interventions may inadvertently stimulate prostate cancer progression.