Sphingosine‑1‑phosphate receptor 1 enhances olfactory receptor 51E1‑mediated inhibition of proliferation via Src/JNK signaling in prostate cancer cells.

Olfactory receptors (ORs) are ectopically expressed in multiple cancers and can regulate tumor cell behavior, yet their clinical relevance and regulatory mechanisms remain poorly defined. OR51E1 is highly expressed in prostate cancer (PC) and suppresses tumor cell proliferation upon activation, but its expression alone does not correlate with patient prognosis, suggesting additional regulatory factors. Using transcriptomic analyses of The Cancer Genome Atlas and Genotype‑Tissue Expression datasets, functional screening of G‑protein‑coupled receptors, and mechanistic studies in PC cells, sphingosine‑1‑phosphate receptor 1 (S1PR1) was identified as a key modulator of OR51E1 function. Activation of OR51E1 by nonanoic acid (NA) or butyric acid reduced PC cell survival in an OR51E1‑dependent manner, and this effect was abolished in OR51E1 knockout cells. S1PR1 enhanced OR51E1‑mediated signaling by increasing its surface expression and amplifying downstream apoptotic responses. Although OR51E1 activation induced cAMP signaling, NA‑induced cytotoxicity was independent of the canonical Gs/olf‑cAMP pathway and instead required Src and JNK activation, which was further potentiated by S1PR1. Clinically, co‑expression of OR51E1 and S1PR1 was significantly associated with improved progression‑free interval in patients with prostate adenocarcinoma, particularly in stage II disease, whereas OR51E1 expression alone showed no prognostic value. Collectively, these findings define a previously unrecognized OR51E1‑S1PR1 signaling axis that suppresses PC cell survival through Src/JNK‑dependent mechanisms and highlight GPCR‑mediated regulation of ectopic olfactory receptors as a determinant of tumor behavior and patient outcome.