Phosphorylation of the androgen receptor is associated with reduced survival in hormone-refractory prostate cancer patients

Abstract

Cell line studies demonstrate that the PI3K/Akt pathway is upregulated in hormone-refractory prostate cancer (HRPC) and can result in phosphorylation of the androgen receptor (AR). The current study therefore aims to establish if this has relevance to the development of clinical HRPC. Immunohistochemistry was employed to investigate the expression and phosphorylation status of Akt and AR in matched hormone-sensitive and -refractory prostate cancer tumours from 68 patients. In the hormone-refractory tissue, only phosphorylated AR (pAR) was associated with shorter time to death from relapse (P ¼ 0.003). However, when an increase in expression in the transition from hormone-sensitive to -refractory prostate cancer was investigated, an increase in expression of PI3K was associated with decreased time to biochemical relapse (P ¼ 0.014), and an increase in expression of pAkt 473 and pAR 210 were associated with decreased disease-specific survival (P ¼ 0.0019 and 0.0015, respectively). Protein expression of pAkt 473 and pAR 210 also strongly correlated (Po0.001, c.c. ¼ 0.711) in the hormone-refractory prostate tumours. These results provide evidence using clinical specimens, that upregulation of the PI3K/Akt pathway is associated with phosphorylation of the AR during development of HRPC, suggesting that this pathway could be a potential therapeutic target.

Is PTEN loss associated with clinical outcome measures in human prostate cancer?

“…All these samples were obtained with 8 weeks of biochemical relapse being diagnosed (two consecutive rises in PSA greater than 10%). Phosphorylated Akt expression is already available for this patient cohort (McCall et al, 2008).…”

“…Expression of phosphorylated Akt at serine 473 (activated Akt) for this cohort of patients had already been established in a previous study (McCall et al, 2008). Levels of phosphorylated Akt expression in tumours that expressed low levels of PTEN was higher compared to tumours that expressed high levels of PTEN (P ¼ 0.047).…”

“…Here, we examined both the deletion of the PTEN gene and expression of PTEN protein at individual cellular locations in a cohort of matched hormone-sensitive and hormone-refractory prostate tumours, with the aim of clarifying the prognostic significance of PTEN loss in prostate cancer. Using the same cohort, we have previously demonstrated that the upregulation of Akt activation is significantly associated with decreased survival, and therefore PTEN loss is one possible route by which this may occur (McCall et al, 2008).…”

Regulation of the androgen receptor by post-translational modifications

“…Caution should also be taken when investigating AR-P in the literature as some of the phosphorylation sites are given different numbers, which can confuse the reader. For example, Ser210 is described as phosphorylated (Lin et al 2001b, McCall et al 2008, Shank et al 2008, Bryant et al 2011; however, when referring to the standard AR protein sequence (ANDR HUMAN, P10275), an arginine is found at this site, while in other studies, the same serine in question is referred to as Ser213 (Wen et al 2000, Nan et al 2003, Burgdorf et al 2004, Taneja et al 2005, Kim & Lee 2009, Lee 2009). In this review, the nomenclature used will correspond to the standard sequence to avoid such confusion.…”

“…The effects of Akt on AR do appear to depend on the number of times cell lines have been passaged; for example, in low passage LNCaP cells Akt inhibits AR, while in high passage cells Akt can activate the AR (Lin et al 2003), which might explain why different functional outcomes are being observed. Upon comparing matched hormone-sensitive and refractory clinical samples of PC in terms of AR-P (Ser213) and the Akt signalling pathway, positive associations between expression and decreased time to death, time to relapse and survival were found (McCall et al 2008). GSK-3b, which is inhibited by Akt-mediated phosphorylation, also mediates AR-P but inhibits transcriptional activity by impeding the interaction between the N and C terminal regions, without affecting localisation or stability (Salas et al 2004.…”