BPH Protein Complex Linked to Potential Treatment Resistance

BPH Protein Complex Linked to Potential Treatment Resistance

Researchers studying the molecular effects of activating a protein complex that controls vital cellular activities — in this case, inflammation — linked it for a first time to an increase in the androgen receptor variant, a receptor present in prostate cells. Overexpression of these molecules is observed in late-stage benign prostatic hyperplasia (BPH), and is associated with potential resistance to a common BPH therapy.

The paper, “NF-kB and Androgen Receptor Variant Expression Correlate With Human BPH Progression,” was published in the journal The Prostate.

BPH is the most common urological condition among older male patients, leading to augmentation of prostate volume that can result in bladder outflow obstruction and a series of lower urinary tract symptoms (LUTS), which diminish a person’s quality of life. BPH comorbidities, or associated illnesses, include systemic inflammation, autoimmune disease, and individual components of metabolic syndrome.

Recent studies of advanced BPH patients have found their gene expression profiles to be similar to those of rheumatoid arthritis and inflammatory bowel disease patients, suggesting that BPH has an autoimmune and inflammatory component. The therapy 5ARI (5 alpha reductase inhibitor) is a common treatment approach for BPH and results in considerable prostate volume reduction, but a number of patients either have no response or develop resistance. Such clinical variability highlights the need for a better understanding of the disease’s molecular mechanism and pathogenicity.

The researchers studied the activation of NF-kB, a transcription factor that regulates the expression of a series of genes involved in inflammation and autoimmunity, and AR-V7, a specific androgen receptor variant whose overexpression in prostate tumors has been shown to be predictive of treatment resistance. The team studied samples from patients who underwent surgery for moderate-to-severe BPH, and from patients with mildly symptomatic BPH.

Results revealed NF-kB signaling was upregulated in more advanced BPH samples compared to earlier-stage ones. Advanced-stage BPH samples also showed an elevated expression of AR-V7. Moreover, induced activation of NF-kB in human prostatic epithelial and stromal cells resulted in increased expression of AR-V7.

Researchers emphasize this is the first study to link chronic activation of NF-kB signaling in BPH to increased AR-V7 expression. In cells where both of these molecules and pathways were upregulated, the viability was maintained, even after 5ARI treatment, indicating resistance to the therapy.

The authors conclude that their observations “provide a potential mechanism to explain the previously observed links between prostatic inflammation and 5ARI resistance, whereby aberrant activation of NF-kB drives AR-V7 expression resulting in ligand independent activation of AR resulting in 5ARI resistance. An understanding of the stress pathways active in individual patients may provide a route to appropriately tailor therapy and avoid the profile of resistance and subsequent progression to surgery that is seen in many patients.”

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