Treating prostate cancer could one day be as noninvasive as inhaling certain scented compounds. The idea may not be as far-fetched as it sounds given that new research from investigators at Duke University School of Medicine shows that an olfactory receptor plays a critical role in the progression of prostate cancer. The researchers found that activating an olfactory receptor called OR51E2 in prostate cancer cells caused the tumor to morph into the more aggressive, castration-resistant form of the disease. Findings from the new study were published recently in Frontiers in Oncology, in an article entitled “A Testosterone Metabolite 19-Hydroxyandrostenedione Induces Neuroendocrine Trans-Differentiation of Prostate Cancer Cells via an Ectopic Olfactory Receptor.”

“When you smell a specific odor, the molecules you inhale go into your bloodstream. So one day, we may be able to use an odorant to cure prostate cancer—though it's not possible yet,” explained senior study investigator Hiroaki Matsunami, Ph.D., professor of molecular genetics and microbiology at Duke University School of Medicine.

When scientists first described the receptors responsible for the sense of smell, they naturally assumed that these chemical sensors resided exclusively in the lining of our noses. However, olfactory receptors then started turning up in the strangest places—lungs, liver, skin, heart, testes, and intestines. More than 25 years later, researchers are still wondering what these receptors are doing in such disparate locations.

Interestingly, the new study results indicate that taking the approach of blocking the receptor with specific molecules, or perhaps even with specific scents, could provide a new way to treat prostate cancer.

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. When the appropriate molecule binds to the receptor, it sets off a cascade of biochemical reactions that culminate in specific biological activity, such as the brain recognizing the scent of freshly cut grass.

Thus far, Dr. Matsunami's lab has identified ligands that activate more than 50 different olfactory receptors, most involved in smell and other senses. The research group was also interested in olfactory receptors that are present outside the nose. The scientists found repeated mentions in the scientific literature of a receptor called OR51E2 that was present in such unusually elevated levels in prostate cancer cells that it earned the alternate moniker prostate-specific G-protein-coupled receptor (PSGR).

To find the ligands that bind OR51E2—the first step to figuring out what role it might play in prostate cancer cells—the Duke team made a virtual model of the olfactory receptor. They then trained a computer to screen a library of 2516 different human metabolites and pick out the ones most likely to unlock the virtual receptor. The scientists took the top 100 most promising candidates from that virtual screen and added them to living cells to see which ones activated the receptor.

A couple of dozen ligands, including a steroid called 19-hydroxyandrostenedione, or 19 OH-AD, caused the cancer cells to take on the characteristics of neuroendocrine cells. Most deaths from prostate cancer are due to the progression of localized disease into metastatic, castration-resistant prostate cancer, 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,” noted lead study investigator Tatjana Abaffy, Ph.D., a research assistant professor at Duke University School of Medicine. “This approach slows down the cancer, but resistance typically develops after a year or two, resulting in castration-resistant prostate cancer. We believe the olfactory receptor is involved at this stage of the disease.”

Remarkably, 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. Yet 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 concluded.

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