Androgen receptor as a licensing factor for DNA replication in androgen-sensitive prostate cancer cells

Abstract

Androgen receptor (AR) protein expression and function are critical for survival and proliferation of androgen-sensitive (AS) prostate cancer cells. Besides its ability to function as a transcription factor, experimental observations suggest that AR becomes a licensing factor for DNA replication in AS prostate cancer cells and thus must be degraded during each cell cycle in these cells to allow reinitiation of DNA replication in the next cell cycle. This possibility was tested by using the AS human prostate cancer cell lines, LNCaP, CWR22Rv1, and LAPC-4. These studies demonstrated that AR levels fluctuate both within and between various phases of the cell cycle in each of these AS lines. Consistent with its licensing ability, AR is degraded during mitosis via a proteasome-dependent pathway in these AS prostate cancer cells. In contrast, proteasome-dependent degradation of AR during mitosis is not observed in AR-expressing but androgen-insensitive human prostate stromal cells, in which AR does not function as a licensing factor for DNA replication. To evaluate mitotic degradation of AR in vivo, the same series of human AS prostate cancers growing as xenografts in nude mice and malignant tissues obtained directly from prostate cancer patients were evaluated by dual Ki-67 and AR immunohistochemistry for AR expression in mitosis. These results document that AR is also down-regulated during mitosis in vivo. Thus, AS prostate cancer cells do not express AR protein during mitosis, either in vitro or in vivo, consistent with AR functioning as a licensing factor for DNA replication in AS prostate cancer cells.cell cycle ͉ prostate stroma

MCM7 Interacts with Androgen Receptor

“…This finding also supports and explains a recent finding that AR functions similar to a licensing factor. 24 The bidirectional effect of AR on MCM7 in LNCaP and PC3 cells with forced expression of AR is consistent with previous findings that a low dosage of androgen induces cell proliferation, whereas a high dosage induces cell growth arrest. 3 It appears that at a high dosage of testosterone, the cell .…”

Orphan nuclear receptor estrogen-related receptor-β suppresses in vitro and in vivo growth of prostate cancer cells via p21WAF1/CIP1 induction and as a potential therapeutic target in prostate cancer

“…These results together with the blockade of cellcycle progression at S phase by ERRb suggest that ERRb may arrest the proliferating cells at G 0 /G 1 phase. Intriguingly, AR also demonstrates a downregulation or degradation pattern during mitosis in androgen-sensitive prostate cancer cells (Litvinov et al, 2006). Besides its well-characterized roles in regulation of prostatic cell growth and differentiation via regulation of its target genes, AR is also shown to play a novel role in DNA replication in prostate cancer cells via a mechanism of forming pre-replicative complexes with some transcriptional co-regulatory proteins at DNA replication foci and such complexes become degraded during mitosis by a proteasome-dependent pathway, thus restricting only one round of DNA replication per cell cycle (Sharma et al, 2003;Huang et al, 2005).…”

The Complex Role of AR Signaling After Cytotoxic Insult: Implications for Cell Cycle Based Chemotherapeutics

“…38 Lastly, it was recently shown that AR is degraded in mitosis; although this latter observation was reported to suggest a putative "licensing" function for AR in controlling DNA replication, this concept has yet to be tested. 39,40 Taken together, it appears that AR principally drives cell cycle progression through modulation of the G 1 -S transition, and that substantive lines of cross-communication between AR and the cell cycle machinery ultimately contribute to the mitogenic action of androgen.…”