Cross-talk between alpha1D-adrenoceptors and transient receptor potential vanilloid type 1 triggers prostate cancer cell proliferation

Abstract

BackgroundThere is evidence that calcium (Ca2+) increases the proliferation of human advanced prostate cancer (PCa) cells but the ion channels involved are not fully understood. Here, we investigated the correlation between alpha1D-adrenergic receptor (alpha1D-AR) and the transient receptor potential vanilloid type 1 (TRPV1) expression levels in human PCa tissues and evaluated the ability of alpha1D-AR to cross-talk with TRPV1 in PCa cell lines.MethodsThe expression of alpha1D-AR and TRPV1 was examined in human PCa tissues by quantitative RT-PCR and in PCa cell lines (DU145, PC3 and LNCaP) by cytofluorimetry. Moreover, alpha1D-AR and TRPV1 colocalization was investigated by confocal microscopy in PCa cell lines and by fluorescence microscopy in benign prostate hyperplasia (BPH) and PCa tissues. Cell proliferation was assessed by BrdU incorporation. Alpha1D-AR/TRPV1 knockdown was obtained using siRNA transfection. Signalling pathways were evaluated by measurement of extracellular acidification rate, Ca2+ flux, IP3 production, western blot and MTT assay.ResultsThe levels of the alpha1D-AR and TRPV1 mRNAs are increased in PCa compared to BPH specimens and a high correlation between alpha1D-AR and TRPV1 expression levels was found. Moreover, alpha1D-AR and TRPV1 are co-expressed in prostate cancer cell lines and specimens. Noradrenaline (NA) induced an alpha1D-AR- and TRPV1-dependent protons release and Ca2+ flux in PC3 cell lines; NA by triggering the activation of phospholipase C (PLC), protein kinase C (PKC) and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways stimulated PC3 cell proliferation, that was completely inhibited by clopenphendioxan (WS433) and capsazepine (CPZ) combination or by alpha1D-AR/TRPV1 double knockdown.ConclusionsWe demonstrate a cross-talk between alpha1D-AR and TRPV1, that is involved in the control of PC3 cell proliferation. These data strongly support for a putative novel pharmacological approach in the treatment of PCa by targeting both alpha1D-AR and TRPV1 channels.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-921) contains supplementary material, which is available to authorized users.

New Multi-target Antagonists of 1A-, 1D-Adrenoceptors and 5-HT1A Receptors Reduce Human Hyperplastic Prostate Cell Growth and the Increase of Intraurethral Pressure

“…Actually, New multi-target Drugs as Potential Leads for BPH Treatment transforming growth factor-b signaling has been considered as one of the mechanisms that contribute to human prostate enlargement (Descazeaud et al, 2011). a 1D -Adrenoceptor mRNA have been shown in human hyperplastic prostate samples (Nasu et al, 1996;Kojima et al, 2006Kojima et al, , 2009aMorelli et al, 2014). Naftopidil, which has 3 and 17 times higher affinity for human a 1D -than for a 1A -and a 1B -adrenoceptors, respectively (Takei et al, 1999), reduces prostate cell growth by arresting cell cycle at G 1 phase (Kojima et al, 2009a,b).…”

A selective alpha1D-adrenoreceptor antagonist inhibits human prostate cancer cell proliferation and motility “in vitro”

“…It should be underlined, however, that the presence of alpha1D-AR only in one of the PC cell lines tested does not ruled out its involvement in PC biology. Indeed, the overexpression of alpha1D-AR in many specimens from untreated patients with advanced PC [16] proves that this AR subtype is a valid target for PC treatment. As PC3 are the only PC cells expressing alpha1D-AR, we selected this cell line to evaluate specifically A175 action.…”

“…As alpha1D-ARs display a prevalent intracellular localization [3,11,42,52], we wondered whether the effect of A175 might either the formation of homo/heterodimers [54], or the crosstalk with other membrane proteins, such as calcium channels [16]. As the majority of the studies on the relationship between alpha1D-AR activity and its cell localization have been conducted in transfected in vitro models [3,52,53], further studies should be undertaken to elucidate the functional role of the endogenous receptor and the mechanism(s) through which selective antagonists counteract its activity.…”

“…Alpha1B-and alpha1D-ARs localize almost exclusively in the epithelial compartment both of normal (PrEc) and neoplastic glands [7,15], where they control cell growth [13]. Remarkably, alpha1D-ARs are overexpressed in androgenresistant PC cells [11] and in specimens from untreated patients with advanced PC [16].…”

Cooperative Interaction between the Alpha1-Adrenoceptors (α1-AR) and Transient Receptor Potential (TRP) Triggers a Proliferative Cell Signal in Prostate Cancer Cell Lines

“…Alpha1-adrenoceptors (α1-ARs) respond to epinephrine (E) and norepinephrine (NE, also called noradrenaline) specific ligands in different target tissues. α1A-AR, α1B-AR and α1D-ARs types are expressed in benign prostate hyperplasia (BHP), PCa, in the androgen-resistant PC3 and DU-145 and androgen-sensitive LNCap cell lines [2,3]. The α1-ARs belong to the G-protein-coupled receptors (GPCRs).…”