Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor

Abstract

Whereas several apoptosis-related proteins have been linked to the antiapoptotic effects of Akt serine-threonine kinase, the search continues to explain the Akt signaling role in promoting cell survival via antiapoptotic effects. Here, we demonstrate that Akt phosphorylates the androgen receptor (AR) at Ser-210 and Ser-790. A mutation at AR Ser-210 results in the reversal of Akt-mediated suppression of AR transactivation. Activation of the phosphatidylinositol-3-OH kinase͞Akt pathway results in the suppression of AR target genes, such as p21, and the decrease of androgen͞AR-mediated apoptosis, which may involve the inhibition of interaction between AR and AR coregulators. Together, these findings provide a molecular basis for cross-talk between two signaling pathways at the level of Akt and AR-AR coregulators that may help us to better understand the roles of Akt in the androgen͞AR-mediated apoptosis.

Isosilybin B causes androgen receptor degradation in human prostate carcinoma cells via PI3K-Akt-Mdm2-mediated pathway

“…Sequence analysis of AR reveals two Akt consensus sequences (RXRXXS/T; Wen et al, 2000), thus Akt can interact directly with AR leading to its phosphorylation (Wen et al, 2000;Lin et al, 2001Lin et al, , 2002. We also observed that isosilybin B treatment results in the activation of Akt as evident by its increased phosphorylation and an increase in Akt kinase activity ( Figure 6b) along with an increased binding between Akt and AR ( Figure 6c).…”

“…Isosilybin B increases the phosphorylation of Akt Akt (60 kDa) is one such kinase whose role has been described in the phosphorylation and degradation of AR (Lin et al, 2001(Lin et al, , 2002. Therefore, we next examined the effect of isosilybin B treatment on Akt phosphorylation.…”

“…As we observed that isosilybin B causes Akt phosphorylation and increases its kinase activity as well, which is involved in AR degradation, and since Akt is known to phosphorylate and degrade AR (Lin et al, 2001(Lin et al, , 2002, we next examined the effect of isosilybin B on phosphorylation status of AR at Ser-210/213 site in presence and absence of PI3K inhibitor. Indeed isosilybin B resulted in an increased phosphorylation of AR at Ser-210/213 site, which was inhibited in the presence of PI3K inhibitor (Figure 6a).…”

“…Various studies have shown the role of glycogen synthase kinase 3b (GSK3b), stress kinase, mammalian target of rapamycin (mTOR) kinase and cyclin-dependent kinase 1 in regulating phosphorylation, stability and localization of AR (Wang et al, 2004;Cinar et al, 2005;Chen et al, 2006;Gioeli et al, 2006). Further, there are numerous studies suggesting the importance of Akt/PKB (a serine/threonine kinase) activation in AR degradation (Lin et al, 2001(Lin et al, , 2002Liao et al, 2005) as well as AR activation (Miyamoto et al, 2005;Reddy et al, 2006); though the interaction of Akt with AR largely remains unclear. Accordingly, we also examined the effect of isosilybin B on Akt phosphorylation and its possible role in AR degradation.…”

Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer

“…Therefore, increased androgen receptor expression, by whatever mechanism, can at best only explain hormone resistance in a subgroup of prostate cancer cases. Alternative mechanisms of hormone resistance are activation of AR via phosphorylation (Zhu and Liu 1997;Lin et al, 2001), therefore increasing AR activity without effecting its expression levels or may bypass the AR, for example, AP-1 phosphorylation (Henttu and Vihko, 1998;Krishna et al, 2002).…”