CACNA1D overexpression and voltage-gated calcium channels in prostate cancer during androgen deprivation

• Published in: Scientific reports 2023-03, Vol.13 (1), p.4683-4683, Article 4683
• Main Authors: McKerr, Niamh, Mohd-Sarip, Adone, Dorrian, Hannah, Breen, Conor, A. James, Jacqueline, McQuaid, Stephen, Mills, Ian G., McCloskey, Karen D.
• Format: Article
• Language: English
• Subjects: 631/443; 631/67; 631/80; Androgen Antagonists - pharmacology; Androgen Antagonists - therapeutic use; Androgen receptors; Androgens; Calcium channels; Calcium channels (voltage-gated); Calcium Channels, L-Type - genetics; Calcium imaging; Cell Line, Tumor; Channel gating; Depolarization; Electrophysiology; Endocrine therapy; Humanities and Social Sciences; Humans; Immunofluorescence; Ion channels; Male; Mibefradil - pharmacology; multidisciplinary; Nifedipine; Nifedipine - pharmacology; Potassium; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-28693-y

Prostate cancer is often treated by perturbing androgen receptor signalling. CACNA1D , encoding Ca V 1.3 ion channels is upregulated in prostate cancer. Here we show how hormone therapy affects CACNA1D expression and Ca V 1.3 function. Human prostate cells (LNCaP, VCaP, C4-2B, normal RWPE-1) and a tissue microarray were used. Cells were treated with anti-androgen drug, Enzalutamide (ENZ) or androgen-removal from media, mimicking androgen-deprivation therapy (ADT). Proliferation assays, qPCR, Western blot, immunofluorescence, Ca 2+ -imaging and patch-clamp electrophysiology were performed. Nifedipine, Bay K 8644 (Ca V 1.3 inhibitor, activator), mibefradil, Ni 2+ (Ca V 3.2 inhibitors) and high K + depolarising solution were employed. CACNA1D and Ca V 1.3 protein are overexpressed in prostate tumours and CACNA1D  was overexpressed in androgen-sensitive prostate cancer cells. In LNCaP, ADT or ENZ increased CACNA1D time-dependently whereas total protein showed little change. Untreated LNCaP were unresponsive to depolarising high K + /Bay K (to activate Ca V 1.3); moreover, currents were rarely detected. ADT or ENZ-treated LNCaP exhibited nifedipine-sensitive Ca 2+ -transients; ADT-treated LNCaP exhibited mibefradil-sensitive or, occasionally, nifedipine-sensitive inward currents. CACNA1D knockdown reduced the subpopulation of treated-LNCaP with Ca V 1.3 activity. VCaP displayed nifedipine-sensitive high K + /Bay K transients (responding subpopulation was increased by ENZ), and Ni 2+ -sensitive currents. Hormone therapy enables depolarization/Bay K-evoked Ca 2+ -transients and detection of Ca V 1.3 and Ca V 3.2 currents. Physiological and genomic CACNA1D /Ca V 1.3 mechanisms are likely active during hormone therapy—their modulation may offer therapeutic advantage.