Identification of Genetic Pathways Activated by the Androgen Receptor during the Induction of Proliferation in the Ventral Prostate Gland

Abstract

The androgen receptor (AR), when complexed with 5␣-dihydrotestosterone (DHT), supports the survival and proliferation of prostate cells, a process critical for normal development, benign prostatic hypertrophy, and tumorigenesis. However, the androgen-responsive genetic pathways that control prostate cell division and differentiation are largely unknown. To identify such pathways, we examined gene expression in the ventral prostate 6 and 24 h after DHT administration to androgen-depleted rats. 234 transcripts were expressed significantly differently from controls (p < 0.05) at both time points and were subjected to extensive data mining. Functional clustering of the data reveals that the majority of these genes can be classified as participating in induction of secretory activity, metabolic activation, and intracellular signaling/signal transduction, indicating that AR rapidly modulates the expression of genes involved in proliferation and differentiation in the prostate. Notably AR represses the expression of several key cell cycle inhibitors, while modulating members of the wnt and notch signaling pathways, multiple growth factors, and peptide hormone signaling systems, and genes involved in MAP kinase and calcium signaling. Analysis of these data also suggested that p53 activity is negatively regulated by AR activation even though p53 RNA was unchanged. Experiments in LNCaP prostate cancer cells reveal that AR inhibits p53 protein accumulation in the nucleus, providing a post-transcriptional mechanism by which androgens control prostate cell growth and survival. In summary these data provide a comprehensive view of the earliest events in AR-mediated prostate cell proliferation in vivo, and suggest that nuclear exclusion of p53 is a critical step in prostate growth.

Expression, regulation and function of the ISGylation system in prostate cancer

“…The tumor suppressor, p53, was postulated as a potential mediator for the regulation of the ISGylation system by androgens (Mitsui et al, 1999;Liu et al, 2004), as (i) AR activation inhibits p53 accumulation in the nucleus (Nantermet et al, 2004) and (ii) p53 was transcriptionally downregulated in LNCaP cells by androgens (Supplementary information 6). By the …”

“…In addition, the chemotherapy-mediated ISG15 induction required a functional p53 protein (Liu et al, 2004), which is also expressed by LNCaP cells. Interestingly, AR activation inhibited p53 accumulation in the nucleus as an early event in androgen-stimulated proliferation (Nantermet et al, 2004), and the androgen stimulation of LNCaP cells mediated a significant downregulation of p53 mRNA and protein through androgen-responsive elements in the p53 gene (Supplementary information 6; Rokhlin et al, 2005), thereby probably promoting the downregulation of the ISGylation components. The Herc5-mediated upregulation by androgens seems to be because of an indirect mechanism of androgen action as no androgen-responsive elements were predicted in a 2000 bp region upstream from the transcription start and within the gene.…”

Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells

“…The relationship between p53 and the androgen axis is complicated since p53 interacts with the AR to disrupt its N-terminal to C-terminal interaction thereby inhibiting DNA-binding activity (Shenk et al, 2001). Androgen also inhibits the expression (Rokhlin et al, 2005) and nuclear accumulation of p53 (Nantermet et al, 2004). Withdrawal of androgen or application of an antiandrogen can increase p53 expression and activity (Agus et al, 1999;Bouchal et al, 2005).…”

Direct cancer tissue proteomics: a method to identify candidate cancer biomarkers from formalin-fixed paraffin-embedded archival tissues

“…We chose Wnt-3 as the Wnt family of proteins is known to cause oncogenic transformation in a number of cell systems including the prostate cells (Nantermet et al, 2004;Verras et al, 2004;Zhu et al, 2004;Cronauer et al, 2005). Recently, Wnt-3-related Wnt-3a protein was shown to support the androgen-independent growth of LNCaP prostate cancer cells (Nantermet et al, 2004;Verras et al, 2004;Zhu et al, 2004;Cronauer et al, 2005). Direct tissue proteomics analysis of prostate cancer-expressed proteins S-I Hwang et al Cronauer et al, 2005).…”