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Alpha1-adrenergic receptors activate Ca(2+)-permeable cationic channels in prostate cancer epithelial cells
Stephanie Thebault1, Morad Roudbaraki, Vadim Sydorenko
1Laboratoire de Physiologie Cellulaire, Institut National de la Santé et de la Recherche Médicale (INSERM) EMI 0228, Villeneuve d'Ascq, France.
Abstract:
The prostate gland is a rich source of alpha1-adrenergic receptors (alpha1-ARs). alpha1-AR antagonists are commonly used in the treatment of benign prostatic hyperplasia symptoms, due to their action on smooth muscle cells. However, virtually nothing is known about the role of alpha1-ARs in epithelial cells. Here, by using two human prostate cancer epithelial (hPCE) cell models - primary cells from resection specimens (primary hPCE cells) and an LNCaP (lymph node carcinoma of the prostate) cell line - we identify an alpha1A subtype of adrenergic receptor (alpha1A-AR) and show its functional coupling to plasmalemmal cationic channels via direct diacylglycerol (DAG) gating. In both cell types, agonist-mediated stimulation of alpha1A-ARs and DAG analogues activated similar cationic membrane currents and Ca(2+) influx. These currents were sensitive to the alpha1A-AR antagonists, prazosin and WB4101, and to transient receptor potential (TRP) channel blockers, 2-aminophenyl borate and SK&F 96365. Chronic activation of alpha1A-ARs enhanced LNCaP cell proliferation, which could be antagonized by alpha1A-AR and TRP inhibitors. Collectively, our results suggest that alpha1-ARs play a role in promoting hPCE cell proliferation via TRP channels.
Insights
Alpha1-adrenergic receptors (alpha1-ARs) in prostate epithelial cells promote cancer growth. Targeting alpha1A-ARs and TRP channels may inhibit prostate cancer cell proliferation.
Area of Science:
- Urology
- Molecular Biology
- Cell Biology
Background:
- Prostate gland expresses alpha1-adrenergic receptors (alpha1-ARs), targeted for benign prostatic hyperplasia.
- The function of alpha1-ARs in prostate epithelial cells remains largely unknown.
Purpose of the Study:
- To investigate the role of alpha1-ARs in human prostate cancer epithelial (hPCE) cells.
- To identify the specific alpha1-AR subtype and its downstream signaling pathways involved in hPCE cell function.
Main Methods:
- Utilized primary hPCE cells and LNCaP cell line.
- Stimulated cells with alpha1A-AR agonists and diacylglycerol (DAG) analogues.
- Measured cationic membrane currents and calcium (Ca2+) influx using specific antagonists and channel blockers.
Main Results:
- Identified alpha1A-adrenergic receptor (alpha1A-AR) in hPCE cells.
- Demonstrated functional coupling of alpha1A-AR to plasmalemmal cationic channels via DAG gating.
- Observed that alpha1A-AR activation enhances LNCaP cell proliferation, inhibited by alpha1A-AR and TRP channel blockers.
Conclusions:
- Alpha1-ARs, specifically the alpha1A subtype, are functionally present in prostate epithelial cells.
- alpha1A-AR signaling promotes hPCE cell proliferation through TRP channels.
- Targeting alpha1A-ARs and TRP channels represents a potential therapeutic strategy for prostate cancer.
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