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A testosterone metabolite 19-hydroxyandrostenedione induces neuroendocrine trans-differentiation of prostate cancer cells via an ectopic olfactory receptor
Abaffy, T., Bain, J. R., Muehlbauer, M. J., Spasojevic, I., Lodha, S., Bruguera, E., O’Neal, S. K., Kim, S. Y., & Matsunami, H. (2018). A testosterone metabolite 19-hydroxyandrostenedione induces neuroendocrine trans-differentiation of prostate cancer cells via an ectopic olfactory receptor. Frontiers in Oncology, 8, 162. Article 162. https://doi.org/10.3389/fonc.2018.00162
Olfactory receptor OR51E2, also known as a Prostate Specific G-Protein Receptor, is highly expressed in prostate cancer but its function is not well understood. Through in silico and in vitro analyses, we identified 24 agonists and 1 antagonist for this receptor. We detected that agonist 19-hydroxyandrostenedione, a product of the aromatase reaction, is endogenously produced upon receptor activation. We characterized the effects of receptor activation on metabolism using a prostate cancer cell line and demonstrated decreased intracellular anabolic signals and cell viability, induction of cell cycle arrest, and increased expression of neuronal markers. Furthermore, upregulation of neuron-specific enolase by agonist treatment was abolished in OR51E2-KO cells. The results of our study suggest that OR51E2 activation results in neuroendocrine trans-differentiation. These findings reveal a new role for OR51E2 and establish this G-protein coupled receptor as a novel therapeutic target in the treatment of prostate cancer.