BackgroundThe androgen receptor (AR) plays a critical role in the proliferation of prostate cancer cells. However, its mechanism of action in proliferation remains unknown. An understanding of the mechanism of AR action in proliferation may lead to the development of effective strategies for the treatment of prostate cancer.Methodology/Principal FindingsIn this study we report that pulse treatment of synchronized LNCaP cells with Casodex, an AR-antagonist, for 4 hours in mid-G1 phase was sufficient to prevent cells from entering S phase. Since the assembly of pre-replication complex (pre-RC) in G1 is required for the progression of cells from G1 to S phase, the effect of Casodex during mid-G1 suggested that the role of AR in proliferation might be to regulate the assembly of pre-RC. To test this possibility, we investigated the interaction between AR and Cdc6, an essential component of pre-RC in LNCaP cells. AR co-localized and co-immunoprecipitated with Cdc6, and Casodex treatment disrupted this interaction. AR-immunoprecipitate (AR-IP) also contained cyclin E and cyclin A, which play a critical role in pre-RC assembly and cell cycle entry into S phase, and DNA polymerase-α, PCNA, and ribonucleotide reductase, which are essential for the initiation of DNA synthesis. In addition, in cells in S phase, AR co-sedimented with components of the DNA replication machinery of cells that entered S phase.Conclusions/SignificanceTogether, these observations suggest a novel role of AR as a component of the pre-RC to exert control over progression of LNCaP cells from G1 to S phase through a mechanism that is independent of its role as a transcription factor.

Background: Androgen receptor (AR) inactivation causes telomere dysfunction. Results: AR-inactivation-induced telomere dysfunction led to the activation of ATM at telomeres, and ATM inhibition blocked repair of damaged telomeric DNA and augmented cell death. Conclusion: ATM promotes survival of AR-inactivated prostate cancer cells with telomere dysfunction. Significance: ATM inhibitors may potentiate the efficacy of AR-targeted therapies for the treatment of prostate cancer.