The activation of OR51E1 causes growth suppression of human prostate cancer cells

Abstract

The development of prostate cancer (PCa) is regulated by the androgen-dependent activity of the androgen receptor (AR). Androgen-deprivation therapy (ADT) is therefore the gold standard treatment to suppress malignant progression of PCa. Nevertheless, due to the development of castration resistance, recurrence of disease after initial response to ADT is a major obstacle to successful treatment. As G-protein coupled receptors play a fundamental role in PCa physiology, they might represent promising alternative or combinatorial targets for advanced diseases. Here, we verified gene expression of the olfactory receptors (ORs) OR51E1 [prostate-specific G-protein coupled receptor 2 (PSGR2)] and OR51E2 (PSGR) in human PCa tissue by RNA-Seq analysis and RT-PCR and elucidated the subcellular localization of both receptor proteins in human prostate tissue. The OR51E1 agonist nonanoic acid (NA) leads to the phosphorylation of various protein kinases and growth suppression of the PCa cell line LNCaP. Furthermore, treatment with NA causes reduction of androgen-mediated AR target gene expression. Interestingly, NA induces cellular senescence, which coincides with reduced E2F1 mRNA levels. In contrast, treatment with the structurally related compound 1-nonanol or the OR2AG1 agonist amyl butyrate, neither of which activates OR51E1, did not lead to reduced cell growth or an induction of cellular senescence. However, decanoic acid, another OR51E1 agonist, also induces cellular senescence. Thus, our results suggest the involvement of OR51E1 in growth processes of PCa cells and its impact on AR-mediated signaling. These findings provide novel evidences to support the functional importance of ORs in PCa pathogenesis.

Regulatory role of G9a and LSD1 in the Transcription of Olfactory Receptors during Leukaemia Cell Differentiation

“…Despite our current data demonstrating an oncogenic function for ORs, several studies have suggested that ORs may act as tumour suppressors24565758. The activation of OR2AT4 and OR51B5 in myelogenous leukaemia K562 cells, decreased proliferation and enhanced apoptosis and differentiation5657.…”

“…The activation of OR2AT4 and OR51B5 in myelogenous leukaemia K562 cells, decreased proliferation and enhanced apoptosis and differentiation5657. In addition, activation of OR51E1 in prostate cancer cells suppressed cell proliferation2458. However, stimulation of ORs was also reported to promote cell invasiveness and metastasis59.…”

Deep Sequencing of the Human Retinae Reveals the Expression of Odorant Receptors

“…Thus, OR mediated signaling pathways may interact with the dopaminergic system in the retina, which regulates the circadian rhythms in the eye as a counterpart to the melatonin system. Dopamine receptors are also involved in cell survival and growth processes in the eye (Witkovsky, 2004) such as ectopically expressed ORs in prostate and keratinocytes (Massberg et al, 2016; Tsai et al, 2016). Interestingly, the expression level of dopamine receptors already described in retina such as D1 receptor ( DRD1 : mFPKM 9) is comparable to that of ORs (Supplementary Figure S11).…”

“…OR2AT4 is another example of the therapeutic potential of ORs in human skin because its activation promotes wound healing processes in human keratinocytes (Busse et al, 2014). They are also of major importance for the regulation of apoptosis, cytokinesis, hormone secretion and differentiation (Braun et al, 2007; Zhang et al, 2012; Maßberg et al, 2015; Gelis et al, 2016; Manteniotis et al, 2016a,b; Massberg et al, 2016; Tsai et al, 2016). However, the expression and localization of ORs in different areas of the brain, the spinal cord, the trigeminal (TG) and dorsal root ganglia (DRG) were recently described (Otaki et al, 2004; Garcia-Esparcia et al, 2013; Flegel et al, 2015; Goncalves et al, 2016).…”

Medium-chain fatty acids modulate myocardial function via a cardiac odorant receptor

“…Additional proof of the anti-OR51E1 antibody specificity is provided by Maßberg et al [59]. However, it should be noted that unspecific binding of the antibody, when tested in heart tissue, cannot be completely excluded due to missing knock-down or knock-out controls.…”