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Rapid signalling by androgen receptor in prostate cancer cells
H Peterziel1, S Mink, A Schonert
1Forschungszentrum Karlsruhe, Institut für Toxikologie und Genetik, Germany.
Abstract:
Androgens are important growth regulators in prostate cancer. Their known mode of action in target cells requires binding to a cytoplasmic androgen receptor followed by a nuclear translocation event and modulation of the expression of specific genes. Here, we report another mode of action of this receptor. Treatment of androgen responsive prostate cancer cells with dihydrotestosterone leads to a rapid and reversible activation of mitogen-activated protein kinases MAPKs (also called extracellular signal-regulated kinases or Erks). Transient transfection assays demonstrated that the androgen receptor-mediated activation of MAP kinase results in enhanced activity of the transcription factor Elk-1. This action of the androgen receptor differs from its known transcriptional activity since it is rapid and insensitive to androgen antagonists such as hydroxyflutamide or casodex. Biochemical studies as well as analyses with dominant negative mutants showed the involvement of kinases such as MAPK/Erk kinase, phosphatidyl-inositol 3-kinase and protein kinase C in the androgen receptor-mediated activation of MAP kinase. These results demonstrate a novel regulatory action of the androgen receptor and prove that in addition to its known transcriptional effects, it also uses non-conventional means to modulate several cellular signalling processes.
Insights
Androgen receptors regulate prostate cancer growth. Beyond gene expression, they rapidly activate mitogen-activated protein kinases (MAPKs), influencing cellular signaling pathways through non-transcriptional actions.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Androgens are key regulators of prostate cancer growth.
- The androgen receptor (AR) typically acts by binding androgens, translocating to the nucleus, and modulating gene expression.
- Prostate cancer cells are androgen-responsive, making AR a critical therapeutic target.
Purpose of the Study:
- To investigate novel modes of androgen receptor (AR) action in prostate cancer cells.
- To explore non-transcriptional signaling pathways regulated by the AR.
- To understand the rapid signaling effects of androgens beyond gene regulation.
Main Methods:
- Treatment of androgen-responsive prostate cancer cells with dihydrotestosterone.
- Transient transfection assays to assess transcription factor activity.
- Biochemical studies and dominant-negative mutant analyses to identify involved kinases.
Main Results:
- Dihydrotestosterone rapidly and reversibly activated mitogen-activated protein kinases (MAPKs/Erks) in prostate cancer cells.
- AR-mediated MAPK activation enhanced the activity of the transcription factor Elk-1.
- This AR action was rapid and insensitive to common androgen antagonists (e.g., hydroxyflutamide, casodex).
- Kinases including MAPK/Erk kinase, phosphatidyl-inositol 3-kinase, and protein kinase C were involved in AR-mediated MAPK activation.
Conclusions:
- The androgen receptor (AR) exhibits a novel mode of action in prostate cancer cells, distinct from its canonical transcriptional role.
- AR rapidly modulates cellular signaling by activating MAPKs through non-transcriptional mechanisms.
- These findings reveal that AR utilizes non-conventional pathways to influence cellular processes, offering new insights into prostate cancer regulation.