Researchers at Duke University in North Carolina have shown that an olfactory receptor plays a critical role in the progression of prostate cancer. This discovery suggests that an approach that aims to block the olfactory receptor with specific molecules, or perhaps even with specific scents – aromatherapy – could become a new therapeutic pathway to fight prostate cancer.

They discovered that the activation of an olfactory receptor called OR51E2 in prostate cancer cells promotes their transformation into a much more aggressive form, one that makes cancer cells hormone-resistant. This discovery suggests that an approach that aims to block the olfactory receptor with specific molecules, or perhaps even with specific scents – could become a new therapeutic pathway to fight prostate cancer.

“When you smell something specific, the molecules you inhale go into your bloodstream. This suggests that someday we may be able to use an odorous molecule to treat prostate cancer – although this is not yet possible,” said Hiroaki Matsunami, Ph.D., senior author of the study and professor of molecular genetics and microbiology at Duke University School of Medicine. The research was published May 28 in Frontiers in Oncology – Genitourinary Oncology

When scientists first described the receptors responsible for our sense of smell, they naturally assumed that these chemical sensors resided exclusively in the lining of our noses.

But then olfactory receptors started turning up in the strangest places — the lungs, liver, skin, heart, testes and intestines. Nearly a quarter of a century later, researchers are still wondering what these receptors are doing in such disparate locations.

Olfactory receptors belong to a family of proteins called G protein-coupled receptors or GPCRs, which are the most commonly exploited drug target in modern medicine. These receptors act by a lock and key mechanism. When the right molecular “key” fits into the receptor’s “lock”, it sets off a cascade of biochemical reactions that culminate in a specific biological activity, such as the brain recognizing the scent of freshly cut grass.

The good molecular “key” is what is called a ligand. A ligand is a molecule that can bind to a receptor. Thus far, Dr. Matsunami’s laboratory has identified the molecular “keys” or ligands that activate more than 50 different olfactory receptors, most involved in smell and other senses.

But Tatjana Abaffy, Ph.D., a research assistant professor working with Dr. Matsunami, was interested in olfactory receptors that are present outside the nose. She found repeated mentions in the scientific literature of a receptor called OR51E2 present in such unusually high levels in prostate cancer cells that it earned the alternate moniker Prostate-Specific G Protein-Coupled Receptor (PSGR).

To find the ligands that bind to the OR51E2 receptor, the first step was to understand its role in prostate cancer cells.

A friend of testosterone shows up

A dozen ligands were selected, including a steroid called 19-hydroxyandrostenedione or 19-OH-AD, a molecule that caused the cancer cells to take on the characteristics of neuroendocrine cells. Most deaths from prostate cancer are due to disease progression, from localized disease into metastatic, resistant to hormone therapy, which is characterized by an increased number of these neuroendocrine-like cells.

“The typical therapy for patients with prostate cancer involves eliminating cancer-fueling hormones like testosterone by chemical or surgical castration,” said Dr, Abaffy, who is lead author of the study. “This approach slows down the cancer, but resistance typically develops after a year or two, resulting in hormone-resistant prostate cancer. We believe the olfactory receptor is involved at this stage of the disease.”

Dr. Abaffy also found that cancer cells secrete 19 OH-AD, which acts as a critical intermediate in the chemical conversion of testosterone into estrogen, essentially feeding their own progression. But when she eliminated the olfactory receptor from the cells, 19 OH-AD lost its effect, and the progression stalled.

“By identifying molecules that can activate or block this receptor, we could change the course of prostate cancer,” Dr. Matsunami said.

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Sources and references
Tatjana Abaffy, James R. Bain, Michael J. Muehlbauer, Ivan Spasojevic, Shweta Lodha, Elisa Bruguera, Sara K. O’Neal, So Young Kim, Hiroaki Matsunami. A Testosterone Metabolite 19-Hydroxyandrostenedione Induces Neuroendocrine Trans-Differentiation of Prostate Cancer Cells via an Ectopic Olfactory Receptor. Frontiers in Oncology, 2018; 8 DOI: 10.3389/fonc.2018.00162

Adapted by PROCURE. © All rights reserved – 2020