Regulatory processes affecting androgen receptor expression, stability, and function: Potential targets to treat hormone‐refractory prostate cancer

Abstract

Prostate cancer cells rely on androgen receptor (AR) for proliferation and survival. Therefore, curing prostate cancer will require elimination of AR. Although androgen is the natural ligand that activates AR, AR activity is also subject to regulation by growth factor/growth factor receptor-stimulated signaling pathways that control the cell cycle. Cell cycle regulatory proteins and protein kinases in signaling pathways affected by growth factors can lead to AR activation in the absence of androgen. While downstream signaling proteins such as cyclins, cyclin-dependent kinases (CDKs), and pRB can modulate AR activity, upstream signaling pathways involving protein kinases such as mitogen-activated protein kinases, protein kinase A, and protein kinase B/Akt can affect post-translational modification of AR to affect not only AR function but also AR stability. Calcium and calmodulin (CaM), essential for proliferation and viability of a number of cells, including prostate cancer cells, play an important role in AR expression, stability, and function. CaM affects AR partly by interacting directly with AR and partly by activating protein kinases such as Akt and DNA-PK that can phosphorylate AR. The ubiquitin/26S proteasome pathway responsible for timely destruction of cell cycle regulatory proteins whose levels impede cell cycle progression also induces AR expression by activating NF-kappaB, and promotes AR activity by participating in the assembly of an AR transcription complex. Maspin, a serine protease inhibitor that is known mostly for its role as a tumor suppressor can also regulate AR intracellular localization and function by competing with AR for binding to the chaperone protein Hsp90 and co-repressor HDAC1, respectively. This perspective reviews the experimental evidence implicating these diverse cellular processes in AR expression, stability, and/or function, and presents a rationale for disrupting these cellular processes as a viable option for the treatment of both the hormone-sensitive and the hormone-insensitive prostate cancer.

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

“…Silybin B exhibited selective partial agonist activity on estrogen-receptor-mediated reporter gene expression (EC25 ¼ 4.4 mM, 30% E2 max induction) and the silymarin mixture exhibits ERb binding activity (Seidlova-Wuttke et al, 2003;Pliskova et al, 2005). Another possibility is that isosilybin B may indirectly influence AR by targeting hsp90 chaperone, hsp90 cochaperones and/or other coregulators of AR, which play important role in proper folding, stability and nuclear translocation of AR (Lee and Chang, 2003b;Reddy et al, 2006). Indeed, these mechanisms and associated biological events require further investigation.…”

“…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 signaling and its interactions with other signaling pathways in prostate cancer

“…EGF has been shown to activate the transcriptional activity of AR by increasing the expression or activity of AR co-activators in prostate cancer cells and, in this way, is thought to promote malignant progression and metastasis of advanced prostate cancer. (52) HER receptor tyrosine kinases 1-4 of the EGFR family are also expressed in prostate cancer cells and their stimulation by EGF and heregulin activates the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K)/Akt pathways (see below, and Fig. 2).…”

Androgen receptor and prostate cancer

“…In an androgen-dependent state, coactivators enhance target gene transcription, whereas increased sensitivity to AR coactivators may be responsible for androgen-independent prostate cancer. 12 Studies of coregulators have revealed differences in expression in CaP; TIF2 and SRC1 were found to be overexpressed in recurrent CaP; further, TIF2 increases the responsiveness of AR to adrenal androgens. 13 Gelsolin increases in CaP after androgen ablation and promotes transactivation in the presence of androgen.…”