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High throughput microscopy identifies bisphenol AP, a bisphenol A analog, as a novel AR down-regulator
Fabio Stossi1, Radhika D Dandekar1, Michael J Bolt1
1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Abstract:
Prostate cancer remains a deadly disease especially when patients become resistant to drugs that target the Androgen Receptor (AR) ligand binding domain. At this stage, patients develop recurring castrate-resistant prostate cancers (CRPCs). Interestingly, CRPC tumors maintain dependency on AR for growth; moreover, in CRPCs, constitutively active AR splice variants (e.g., AR-V7) begin to be expressed at higher levels. These splice variants lack the ligand binding domain and are rendered insensitive to current endocrine therapies. Thus, it is of paramount importance to understand what regulates the expression of AR and its splice variants to identify new therapeutic strategies in CRPCs. Here, we used high throughput microscopy and quantitative image analysis to evaluate effects of selected endocrine disruptors on AR levels in multiple breast and prostate cancer cell lines. Bisphenol AP (BPAP), which is used in chemical and medical industries, was identified as a down-regulator of both full length AR and the AR-V7 splice variant. We validated its activity by performing time-course, dose-response, Western blot and qPCR analyses. BPAP also reduced the percent of cells in S phase, which was accompanied by a ~60% loss in cell numbers and colony formation in anchorage-independent growth assays. Moreover, it affected mitochondria size and cell metabolism. In conclusion, our high content analysis-based screening platform was used to classify the effect of compounds on endogenous ARs, and identified BPAP as being capable of causing AR (both full-length and variants) down-regulation, cell cycle arrest and metabolic alterations in CRPC cell lines.
Insights
Bisphenol AP (BPAP) down-regulates androgen receptor (AR) and AR-V7 in prostate cancer cells. This compound also halts cell cycle progression, reduces cell numbers, and alters cell metabolism, offering new therapeutic avenues for castrate-resistant prostate cancer.
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.
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