Protein that Suppresses Androgen Receptors Could Improve Prostate Cancer Diagnosis and Treatment
News May 21, 2009
A protein that helps regulate expression of androgen receptors could prove a new focal point for staging and treating testosterone-fueled prostate cancer, Medical College of Georgia researchers say.
Levels of the protein, ßarrestin2, are lower in some prostate cancer cells than in normal prostate cells while expression of testosterone-fed androgen receptors is higher, they report in Proceedings of the National Academy of Sciences Online Early Edition this week.
"An increase in the number of androgen receptors is believed responsible for prostate cancer progression in men with advanced disease," says the study's corresponding author, Dr. Yehia Daaka, Distinguished Chair in Oncologic Pathology in the MCG School of Medicine.
With increased numbers of androgen receptors, prostate cancer can make use of the limited testosterone available after a diseased prostate gland is removed or after testosterone production is blocked by drug therapy. In fact, the increased number of androgen receptors may mutate so they can start feeding off other steroids or even growth factors, Dr. Daaka says.
These wily skills help explain why cancer returns despite initially promising treatment results.
"It is clear that signaling by the androgen receptor is paramount for not only the initiation but also the progression of the disease, including escape to a hormone-refractory disease," he says. Moves androgen receptors make to support cancer growth make it "unbeatable at this point," for some patients.
However increased levels of ßarrestin2 appear to halt the potentially deadly increase in androgen receptor expression, the MCG research team has found.
Androgen receptors have co-factors that can activate or repress their activity. "You could make the leap and say perhaps prostate cancer initiation and progression may be regulated by expression or non-expression of these co-factors," says Dr. Daaka, a Georgia Cancer Coalition Distinguished Cancer Scholar.
Their studies in human tissue - both in culture and transplanted into mice - show this appears the case for ßarrestin2. First the team identified ßarrestin2 as cofactor for androgen receptors. Next they found a reciprocal relationship: androgen receptor expression is low when ßarrestin2 expression increases. That's the scenario in healthy prostate cells while the exact opposite is true in some prostate cancer. When they forced increased expression of ßarrestin2, androgen receptor expression and activity went down.
ßarrestin2 locks up an androgen receptor by binding to it, then the pair bind to yet another protein, ubiquitin ligase, which tags the receptor as waste and the trio make their way to the cell's garbage dump. "The neat thing about it is ßarrestin2 inhibits or blunts the androgen receptor by promoting its degradation. So it disappears," Dr. Daaka says.
His future studies include determining what happens when ßarrestin2 expression is further decreased in the face of prostate cancer. These studies will also help determine how big a player ßarrestin2 is in prostate cancer progression, says Dr. Daaka, noting that numerous other corepressors and activators of androgen receptors are known.
Prostate- and Colon Cancer Targeted With Tapeworm DrugNews
Recently researchers found that a substance in medicine against parasites like Giardia and Tapeworms, acts like tailored medicine against prostate- and colon cancer.READ MORE
New Player in Alzheimer's Disease Pathogenesis IdentifiedNews
Using proteomics, microscopic analysis, and functional assays, scientists have shown that a protein called membralin is critical for keeping Alzheimer’s disease pathology in check.READ MORE
Proteome of the Human Heart Mapped for the First TimeNews
Scientists have determined which and how many individual proteins are present in each type of cell that occurs in the heart. In doing so, they compiled the first atlas of the healthy human heart, known as the cardiac proteome. The atlas will make it easier to identify differences between healthy and diseased hearts in future.READ MORE