Inhibition of MAPK-signaling pathway promotes the interaction of the corepressor SMRT with the human androgen receptor and mediates repression of prostate cancer cell growth in the presence of antiandrogens

Abstract

Prostate cancer is one of the most prominent malignancies of elderly males. The growth of normal prostate and prostate cancer (PCa) cells depend on functional androgen receptor (AR), a ligand controlled transcription factor and member of the nuclear receptor superfamily. Binding of agonistic ligand enhances the transactivation function of AR and hence promotes the growth of prostate epithelial cells. We have earlier shown that AR antagonistic ligands such as cyproterone acetate (CPA) promote the recruitment of transcriptional corepressors such as silencing mediator of retinoid and thyroid receptor (SMRT) leading to repression of AR transactivation in non-PCa cells. Unfortunately, however, in LNCaP PCa cells, CPA functions as an agonist and thereby increases AR transactivation function. Here, we show that activated MEK signaling cascade inhibits functional recruitment of corepressor SMRT to CPA-bound AR in PCa cells. Chemical blockade of MEK kinase using a specific inhibitor U0126 increases the interaction and hence repression of AR by the corepressor SMRT in LNCaP PCa cells. This inhibition also results in enhanced antagonistic behavior of CPA as assessed by reporter and cell-growth assays. Moreover, the growth of LNCaP cells stably overexpressing SMRT was more robustly inhibited in the presence of CPA and U1026. In line with this, the growth rate of LNCaP cells was decelerated in the presence of both CPA and U0126. This suggests that activated MEK signaling pathway attenuates the functional recruitment of corepressor SMRT to AR induced by antagonists and thus indicates the important role of corepressors in mediating repression of both AR transactivation and PCa cell growth by antagonists. Furthermore, these findings suggest that combining receptor antagonists with signaling inhibitors could be a beneficial approach for PCa treatment.

Corepressor effect on androgen receptor activity varies with the length of the CAG encoded polyglutamine repeat and is dependent on receptor/corepressor ratio in prostate cancer cells

“…In this manner, corepressors would play a key role in conferring agonist or antagonist capacity. The data in this study supports the recognition that SMRT and NCOR1 can bind AR in the presence of agonist ligands such as DHT (Hodgson et al 2005; Yoon and Wong 2006), thereby dampening the receptor’s ability to activate gene transcription and thereby promote prostate cancer cell growth (Eisold et al 2009). Indeed, numerous microarray and functional studies have demonstrated that agonist-activated steroid receptors are as likely to repress transcription as activate it (Cunliffe 2008; Perissi et al 2010; Yoon and Wong 2006).…”

The natural compounds atraric acid and N-butylbenzene-sulfonamide as antagonists of the human androgen receptor and inhibitors of prostate cancer cell growth

“…However, antihormone treatment is effective only for a limited period of about 16-24 months after which PCa becomes androgen-independent (Feldman et al, 2001;Eisold et al, 2009).…”

Targeting transcription factor corepressors in tumor cells

“…NCoR1/SMRT bind to both agonist-and antagonist-bound ARs, which lessens the receptor's tumor-promoting ability [21,22]. Activated MAPK cascade may attenuate the corepressor recruitment [23]. Additionally, certain regions on the AR may influence the degree of the complex binding and concomitantly favoring coactivators [24].…”