Role of Androgen Receptor in Progression of LNCaP Prostate Cancer Cells from G1 to S Phase

Abstract

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.

The role of epithelial plasticity in prostate cancer dissemination and treatment resistance

“…The AR pathway is activated by 5α-dihydrotestosterone (DHT), a metabolite of testosterone, and binding of DHT to AR initiates translocation of the nucleus, where AR acts as a transcription factor to transcribe genes involved in cell cycle progression [64]. Importantly, androgens can also modulate EMT in some PC cell lines.…”

Anti-cancer effects of torulene, isolated from Sporidiobolus pararoseus, on human prostate cancer LNCaP and PC-3 cells via a mitochondrial signal pathway and the down-regulation of AR expression

“…With the consideration of the high failure rates and predictable ineffectiveness of the treatment, novel targets are urgently required depending on the presence or absence of functional AR status. [6][7][8] Apoptosis is a naturally occurring process of programmed cell death. Many plant-origin chemotherapy drugs can promote apoptosis of cancer cells, and some signal pathways are involved in the process.…”

“…6 Torulene, one of the most principal carotenoid in Sporidiobolus pararoseus, has 13 conjugated double bonds, and the differences of structure between it and lycopene are subtle. However, it has not been well-studied with respect to its bioactivity and nutritional function.…”

ATM Inhibition Potentiates Death of Androgen Receptor-inactivated Prostate Cancer Cells with Telomere Dysfunction

“…These observations raise an intriguing possibility that AR may play a role in telomere DNA replication or repair and that aberrant telomeres in AR-inactivated prostate cancer cells may result from impaired telomere DNA replication or repair. Consistent with this possibility are the observations that AR co-immunoprecipitates with TRF-1 and TRF-2 (3), AR is associated with telomere DNA (4), and AR is implicated to play a non-transcriptional role in DNA replication (36,45) and possibly in repair of nuclear DNA (46). However, it remains to be determined whether AR inactivation interferes with either replication or repair of telomere DNA.…”