A Testosterone Metabolite 19-Hydroxyandrostenedione Induces Neuroendocrine Trans-Differentiation of Prostate Cancer Cells via an Ectopic Olfactory Receptor

  • Front Oncol. 2018 May 28:8:162. doi: 10.3389/fonc.2018.00162.
Tatjana Abaffy  1 ,  James R Bain  2 ,  Michael J Muehlbauer  2 ,  Ivan Spasojevic  3 ,  Shweta Lodha  4 ,  Elisa Bruguera  4 ,  Sara K O'Neal  2 ,  So Young Kim  5 ,  Hiroaki Matsunami  6
Affiliations
  • 1. Department of Molecular Genetics and Microbiology, Duke Cancer Institute, Duke University School of Medicine, Durham, NC, United States.
  • 2. Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, United States.
  • 3. Department of Medicine, Duke University School of Medicine, Durham, NC, United States.
  • 4. Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, United States.
  • 5. Department of Molecular Genetics and Microbiology, Functional Genomics Shared Resource, Duke University School of Medicine, Durham, NC, United States.
  • 6. Department of Molecular Genetics and Microbiology, Department of Neurobiology, Duke Institute for Brain Sciences, Duke Cancer Institute, Duke University School of Medicine, Durham, NC, United States.
PMID: 29892571 DOI: 10.3389/fonc.2018.00162
Abstract

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.

Keywords
19-hydroxyandrostenedione; OR51E2; PSGR; agonists; neuroendocrine trans-differentiation; neuron-specific enolase; olfactory receptor; prostate cancer.
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