High throughput microscopy identifies bisphenol AP, a bisphenol A analog, as a novel AR down-regulator

Area of Science:

• Oncology
• Molecular Biology
• Endocrinology

Background:

• Prostate cancer (PCa) is a deadly disease, particularly when it becomes resistant to endocrine therapies targeting the Androgen Receptor (AR).
• Castrate-resistant prostate cancer (CRPC) often exhibits increased expression of AR splice variants, such as AR-V7, which lack the ligand-binding domain and are insensitive to current treatments.
• Understanding the regulation of AR and its variants is crucial for developing novel therapeutic strategies for CRPC.

Purpose of the Study:

• To identify compounds that modulate Androgen Receptor (AR) levels and activity in prostate cancer cells, including those resistant to endocrine therapy.
• To investigate the effects of identified compounds on cell cycle progression, proliferation, and metabolism in CRPC models.

Main Methods:

• High-throughput microscopy and quantitative image analysis were employed to screen endocrine disruptors for their effects on AR levels.
• Bisphenol AP (BPAP) was identified and further validated using time-course, dose-response, Western blot, and qPCR analyses.
• Cell cycle analysis, cell counting, colony formation assays, and metabolic assessments were performed to evaluate BPAP's impact.

Main Results:

• Bisphenol AP (BPAP) was identified as a potent down-regulator of both full-length AR and the AR-V7 splice variant in multiple cancer cell lines.
• BPAP treatment led to a reduction in S-phase cell population, a significant decrease in cell numbers (~60%), and impaired colony formation.
• The compound also induced alterations in mitochondrial size and cellular metabolism.

Conclusions:

• A high-content screening platform effectively identified compounds affecting endogenous AR expression.
• Bisphenol AP (BPAP) demonstrates significant potential by down-regulating AR (full-length and variants), inducing cell cycle arrest, and altering metabolism in CRPC cell lines.
• These findings suggest BPAP as a promising candidate for further investigation in the development of new therapies for castrate-resistant prostate cancer.