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Regulation Of Androgen Receptor Levels By A Feedback Loop In Prostate Cancer Cells
Albert Dobi
CPDR, Rockville, MD
Introduction: Elevation in androgen receptor levels are commonly observed in prostate cancer cells that may be due to decreased expression of rate-limiting factors of protein degradation pathways. Our objective is to investigate if the ubiquitin ligase docking protein, PMEPA1, that expression is frequently decreased or lost in prostate cancer can facilitate AR degradation through the ubiquitin-proteasomal degradation pathway. Intriguingly, PMEPA1 gene expression is regulated by androgens. Therefore, our long-term goal is to reveal the regulatory circuit between AR and PMEPA1.
Materials and Methods: PMEPA1 protein was overexpressed in stable transfectant tet(-)-inducible LNCaP cells and AR levels were monitored by immunoblot assay. To evaluate the involvement of protealsomal degradation pathway in AR and PMEPA1 levels, prostate cancer cells were treated with proteasome inhibitor and protein levels were assayed by immunoblotting. Chromatin immunoprecipitation was used for monitoring androgen dose-dependent AR binding to the PMEPA1 promoter. PMEPA1 gene expression was assessed by Real-Time PCR.
Results: PMEPA1 over expression resulted in dramatic decreases in AR levels. Proteasomal inhibitor treatment rescued PMEPA1-mediated AR loss in LNCaP cells.
AR activated the PMEPA1 promoter in a hormone dose-dependent manner and upregulated PMEPA1 expression.
Conclusion: Ligand bound AR can upregulate the expression of PMEPA1 gene on the transcription level and PMEPA1 protein facilitates the degradation of AR through the ubiquitin-proteasome pathway that suggests a feedback loop for the regulation of AR protein levels. Lost or decreased expression of PMEPA1 in prostate cancer specimens may contribute to the elevation of AR levels during cancer progression.
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