Ectopically expressed olfactory receptors OR51E1 and OR51E2 suppress proliferation and promote cell death in a prostate cancer cell line

Abstract

Olfactory receptors (ORs), the largest family of G protein–coupled receptors, are expressed in the nasal epithelium where they mediate the sense of smell. However, ORs are also found in other non-nasal tissues, but the role of these ectopic ORs in cell signaling, proliferation, and survival is not well understood. Here, using an inducible expression system in the lymph node carcinoma of the prostate (LNCaP) cell line, we investigated two ectopic ORs, OR51E1 and OR51E2, which have been shown to be upregulated in prostate cancer. We found that, consistent with previous studies, OR51E1 stimulated adenylyl cyclase in response to treatment by short-chain to medium-chain organic acids (C3–C9) but not by acetate. OR51E2 responded to acetate and propionate but not to the longer chain organic acids. Stimulation of LNCaP cells with butyrate inhibited their growth, and the knockdown of the endogenous OR51E1 negated this cytostatic effect. Most significantly, overexpression of OR51E1 or OR51E2 suppressed LNCaP cell proliferation. Overexpression of another ectopic OR OR2AT4, β2-adrenergic receptor, or treatment of cells with forskolin did not suppress cell proliferation, indicating that a rise in cAMP is not sufficient to induce cytostasis. Overexpression of OR51E1 caused an upregulation of cytostatic and cell death markers including p27, p21, and p53, strongly increased annexin V staining, and stimulated extracellular signal–regulated protein kinases 1 and 2. Overexpression and/or activation of OR51E1 did not affect human embryonic kidney 293 cell proliferation, indicating that cytotoxicity of OR51E1/OR51E2 is specific for LNCaP cells. Together, our results further our understanding of prostate cancer etiology and suggest that ectopic ORs may be useful therapeutic targets.

The Olfactory Receptor Gene Product, OR5H2, Modulates Endometrial Cancer Cells Proliferation via Interaction with the IGF1 Signaling Pathway

“…While our data and that of others suggest a proliferative, anti-apoptotic role for ORs, other studies are consistent with a tumor suppressing role for members of this family. Thus, ectopically expressed OR51E1 and OR51E2 suppressed prostate cancer cells growth in association with the upregulation of cytostatic and cell death markers, including p27, p21 and p53, and enhanced annexin V staining [46]. Taken together, ORs display organ-specific, concentration-dependent bioactivities.…”

Functional analysis of human olfactory receptors with a high basal activity using LNCaP cell line

“…OR1A2 is expressed in HuH7 cells, and it is sensitive to (-)-citronellal and citronellol [ 46 ]. LNCaP cells express OR51E1 and OR51E2 (also named prostate-specific G-protein-coupled receptor [PSGR]), which recognize β-ionone, propionic acid, butyric acid, and nonanoic acid [ 47 , 48 ]. As HepG2, HuH7, and LNCaP have not been widely utilized as functional expression systems for GPCRs, we first screened several experimental conditions, such as transfection reagents and culture buffers, based on the responsiveness of OR1A1 ( S1 Fig ).…”

Orphan receptors in prostate cancer

“…The full spectrum of their ligands is still unknown, but deorphanization efforts showed that they can be activated by lactate, butyric acid, propionic acid, and other aliphatic acids. 23 The activation of OR51E2 by the ligand beta-ionone leads to inhibition of prostate cancer cell proliferation, by blocking the AR nuclear translocation. 21 However, Sanz et al showed that beta-ionone stimulation of OR51E2 in LNCaP cells promotes a PI3K-gamma-dependent increase in tumor invasiveness and metastatic potential.…”

“…53 In addition, changes in OR51E2 expression have been associated with activation of nuclear factor-kappa B and protein kinases. 23 OR51E2 is expressed in normal prostate epithelial tissue, which suggests that it might play a physiological role. 54 Moreover, experiments have shown that the activation of OR51E1 inhibits cell proliferation and induces senescence in prostate cancer.…”