Title : From marker to mechanism: Ligand discovery enables functional analysis of OR51E1, an ectopic olfactory receptor, in prostate cancer
Abstract:
OR51E1 is a G protein-coupled receptor that belongs to the family of olfactory receptors, but is found in a few tissues outside the nasal epithelium. It widely reported as a prostate cancer–associated marker, yet its functional role has remained unclear due to the lack of adequate pharmacological tools. We developed a high-throughput screening platform combined with computational hit expansion and identified novel synthetic OR51E1 agonists and antagonists with substantially improved potency and specificity over previously proposed endogenous ligands. These novel compounds enabled direct manipulation of OR51E1 signaling in human prostate cancer cells expressing the receptor endogenously. Receptor activation promotes invasion, anchorage-independent growth, and other behaviors associated with metastatic progression, whereas antagonists suppress these phenotypes, linking OR51E1 signaling to pro-tumorigenic cellular programs. These findings move the field beyond correlative studies and establish cause–effect relationships between OR51E1 activity and cancer-relevant cell behaviors. Together, this work identifies OR51E1 as a driver of prostate cancer and suggests that antagonists targeting this receptor may help delay or prevent disease progression. More broadly, our findings establish ectopically expressed olfactory receptors as a previously underappreciated receptor class that is accessible to both mechanistic analysis and pharmacological intervention.
