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

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.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.3389/fonc.2018.00162

Publication Info

Abaffy, Tatjana, James R Bain, Michael J Muehlbauer, Ivan Spasojevic, Shweta Lodha, Elisa Bruguera, Sara K O'Neal, So Young Kim, et al. (2018). A Testosterone Metabolite 19-Hydroxyandrostenedione Induces Neuroendocrine Trans-Differentiation of Prostate Cancer Cells via an Ectopic Olfactory Receptor. Frontiers in oncology, 8(MAY). p. 162. 10.3389/fonc.2018.00162 Retrieved from https://hdl.handle.net/10161/17219.

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Scholars@Duke

Bain

James R. Bain

Professor in Medicine
Spasojevic

Ivan Spasojevic

Associate Professor in Medicine
Kim

So Young Kim

Associate Research Professor in Molecular Genetics and Microbiology

I serve as Director of the Duke Functional Genomics Core Facility, where our central mission is to provide resources for high-throughput analysis of gene function and small molecule screens for drug discovery. Our core works with Duke investigators to provide the expertise, infrastructure and libraries necessary for these screens and can collaborate on all stages of the screening project, including study design, assay optimization and data analysis. The facility also provides services for custom cell line engineering using techniques including CRISPR knockouts/knockins, RNAi gene suppression and ORF expression. Our lab is also interested in collaborating with investigators to develop and improve existing methodologies to enhance the utility of functional genomics tools within the lab. 

I am also the Director of the Duke Microbiome Core Facility, which supports the research of investigators seeking to uncover the roles that microbiomes play in human health and the environment. The core provides assistance with study design, sample management, DNA extractions, NGS library prep and data analysis. The lab is also interested in developing new techniques and analysis tools to better assess microbiome composition across a range of sample types.

Matsunami

Hiroaki Matsunami

Professor of Molecular Genetics and Microbiology

We are interested in the molecular mechanisms underlying chemosensation (taste and smell) in mammals. The receptors that detect odorants, pheromones, and many tastants including bitter and sweet chemicals are G-protein coupled receptors (GPCRs), which typically have seven transmembrane domains. There are many important questions that are still unanswered in chemosensory neurobiology. How do tens of thousands of different chemicals (tastants, odorants, or pheromones) interact with more than one thousand chemosensory receptors (about 1000 odorant receptors, 40 taste receptors and 200 vomeronasal receptors in the case of mice or rats)? How is the information coded in sensory cells and in the brain? How does the brain direct appropriate behavioral responses? What are the mechanisms underlying development and regeneration of sensory cells and specific synapse connections? We address these questions using molecular biology, genome information and genetics.

The detection of tastants is mediated by taste receptor cells that are clustered in taste buds in the mouth. Interestingly, some people can taste certain chemicals, such as 6-n-propylthiouracil (a bitter compound) while others can't. Likewise, some strains of mice can taste certain bitter or sweet tastants while others can't. Based on these variations, the bitter and sweet taste loci have been mapped on human or mouse chromosomes. By using the increasingly powerful genome informatics tools, we as well as other groups, have identified families of GPCRs that may detect bitter and sweet compounds. We seek to understand how specific changes in nucleotide sequences cause these differences in taste sensitivity. Another goal is to understand how the gustatory system is organized.

In olfaction, the detection of volatile odorants is mediated by olfactory sensory neurons in the olfactory epithelium of the nose. Odorants are detected by about 1000 different types of odorant receptors that are encoded by a multigene family. Each olfactory sensory neuron expresses only one receptor type out of 1000 receptors. Axons of neurons expressing the same receptor all converge in a few glomeruli in the olfactory bulb of the brain. We wish to understand the mechanisms underlying this convergence.

Finally, we are interested in the pheromone sensing system. Pheromones are chemicals that are released from animals and induce innate behavior, such as mating or aggression, or hormonal changes in members of the same species.
The detection of pheromones is mediated primarily by a second olfactory sense organ, called the vomeronasal organ (VNO). We, as well as other groups, have found families of candidate pheromone receptors by comparing gene expression between single VNO neurons. Pheromone molecules may induce their effects by activating some of these receptors, which ultimately affect particular regions of the brain. We seek to understand how these pheromonal effects are mediated.


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