Activation of an Olfactory Receptor Inhibits Proliferation of Prostate Cancer Cells

Abstract

Olfactory receptors (ORs) are expressed not only in the sensory neurons of the olfactory epithelium, where they detect volatile substances, but also in various other tissues where their potential functions are largely unknown. Here, we report the physiological characterization of human OR51E2, also named prostate-specific G-protein-coupled receptor (PSGR) due to its reported up-regulation in prostate cancer. We identified androstenone derivatives as ligands for the recombinant receptor. PSGR can also be activated with the odorant ␤-ionone. Activation of the endogenous receptor in prostate cancer cells by the identified ligands evoked an intracellular Ca 2؉ increase. Exposure to ␤-ionone resulted in the activation of members of the MAPK family and inhibition of cell proliferation. Our data give support to the hypothesis that because PSGR signaling could reduce growth of prostate cancer cells, specific receptor ligands might therefore be potential candidates for prostate cancer treatment.Excessive signaling by G-protein-coupled receptors (GPCRs) 3 such as endothelin A receptor (1), bradykinin 1 receptor (2), follicle-stimulating hormone receptor (3), and thrombin receptor (4, 5) is known to occur in prostate cancers due to strong overexpression of the respective receptors. Activation of some of these GPCRs results in androgen-independent androgen receptor activation, thus promoting the transition of prostate cancer cells from an androgen-dependent to an androgen-independent state (6, 7).The prostate-specific G-protein-coupled receptor (PSGR) is a class A GPCR that was initially identified as a prostate-specific tumor biomarker (8 -10). It is specifically expressed in prostate epithelial cells, and its expression increases significantly in human prostate intraepithelial neoplasia and prostate tumors, suggesting that PSGR may play an important role in early prostate cancer development and progression (9, 11). Although expression of the human PSGR was found to be prostate-specific (10, 12), mRNA can also be detected in the olfactory zone and the medulla oblongata of the human brain (12). Human PSGR shares 93% amino acid homology to the respective mouse and rat homologues, which are also expressed in the brain (12). Interestingly, PSGR has numerous sequence motifs in common with the large superfamily of olfactory receptors (ORs), which build the largest class of human GPCRs and allow the recognition of a wide range of structurally diverse molecules in the nasal epithelium (13-15). Recently, also the steroid hormones androstenone and androstadienone were identified as OR ligands (16). In addition to their role in the sensory neurons of the nose, ORs have been found in different tissues throughout the body (17,18). Their function(s) in these extranasal locations are questionable except for in a few cases where functional studies have been performed in spermatozoa (19,20) and in enterochromaffin cells of the gastrointestinal tract (21).Here, we report the identification of steroid ligands of heterologously expressed PSGR...

Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation

“…We were unable to detect a response to β-ionone for Olfr78 or OR51E2 in our luciferase-based reporter assay, and β-ionone also failed to elicit changes in BP when delivered intravenously. It is possible that this difference stems from the different methods used; Neuhaus et al (32) used a calcium imaging method to detect odorant responses, whereas we assayed cAMP (via luciferase). We did, however, confirm in a separate assay that activation of Olfr78 and OR51E2 by acetate or propionate produces a signal detectable by calcium imaging.…”

Olfactory Receptor Family 7 Subfamily C Member 1 Is a Novel Marker of Colon Cancer–Initiating Cells and Is a Potent Target of Immunotherapy

“…Several kinds of olfactory receptors have been identified in tissues other than olfactory tissues, including the testis, tongue, and placenta; however, functions of most olfactory receptors expressed in nonolfactory tissues are still elusive (28). A previous study showed that an olfactory receptor, OR51E2, is expressed in prostate cancer cells and that activation of OR51E2 by its ligand, b-ionone and inhibited proliferation of prostate cancer cells (29). Another olfactory receptor family member, OR51E1, was reported to be a potential novel biomarker for small intestine neuroendocrine carcinoma (30).…”

“…As OR7C1 is expressed in primary spermatocytes, secondary spermatocytes, spermatid, and sperm in the testis, it may have a role in sperm chemotaxis. Inactivation of OR51E2 could reduce growth of prostate cancer cells via this pathway and then phosphorylation of p38 and stress-activated protein kinase/c-Jun NH 2 -terminal kinase (SAPK/JNK) MAPKs (29). The signaling pathway that induces the expression of stem cell-related genes via OR7C1 is still elusive, but activation of adenylate cyclase by Golf might be a possible pathway, and our preliminary data suggested that activation of Akt might also be involved in OR7C1 signal transduction (data not shown).…”

Modeling of mammalian olfactory receptors and docking of odorants

“…Beginning in 2000, ORs have been repeatedly reported also to be expressed in non-olfactory tissues (De la Cruz et al 2009;Feldmesser et al 2006;Zhang et al 2007) where they play additional roles. Some ORs govern sperm chemotaxis (Fukuda and Touhara 2006;Spehr et al 2004), inhibit prostate cancer cell proliferation (Neuhaus et al 2009), regulate cell migration and adhesion in muscle (Griffin et al 2009), and regulate serotonin secretion of gastro-intestinal cells (Braun et al 2007;Kidd et al 2008). ORs are also reported to be tumor markers (Leja et al 2009;Weng et al 2005).…”