NF-κB Regulates Androgen Receptor Expression and Prostate Cancer Growth

Abstract

Prostate cancers that progress during androgen-deprivation therapy often overexpress the androgen receptor (AR) and depend on AR signaling for growth. In most cases, increased AR expression occurs without gene amplification and may be due to altered transcriptional regulation. The transcription factor nuclear factor (NF)-B, which is implicated in tumorigenesis, functions as an important downstream substrate of mitogen-activated protein kinase, phosphatidylinositol 3-kinase, AKT, and protein kinase C and plays a role in other cancer-associated signaling pathways. NF-B is an important determinant of prostate cancer clinical biology, and therefore we investigated its role in the regulation of AR expression. We found that NF-B expression in prostate cancer cells significantly increased AR mRNA and protein levels, AR transactivation activity, serum prostate-specific antigen levels, and cell proliferation. NF-B inhibitors decrease AR expression levels, prostate-specific antigen secretion, and proliferation of prostate cancer cells in vitro. Furthermore , inhibitors of NF-B demonstrated anti-tumor activity in androgen deprivation-resistant prostate cancer xenografts. In addition , levels of both NF-B and AR were strongly correlated in human prostate cancer. Our data suggest that NF-B can regulate AR expression in prostate cancer and that NF-B inhibitors may have therapeutic potential.

Molecular genetics of prostate cancer: new prospects for old challenges

“…The consequences of Akt activation are mediated in part by activation of NF-kB signaling via stimulation of IKK (Dan et al 2008). Conversely, functional studies in mouse models and correlative studies in human prostate cancer have implicated deregulated NF-kB signaling in mediating androgen responsivity, metastasis, and disease outcome (Fradet et al 2004;Ismail et al 2004;Lessard et al 2006;Luo et al 2007;Zhang et al 2009). …”

Tumor protein D52 (isoform 3) contributes to prostate cancer cell growth via targeting nuclear factor-κB transactivation in LNCaP cells

“…Previous studies have shown that PKB/Akt can activate NF-κB in castration-resistant PCa. 42,50,59 Therefore, we made an attempt to elucidate detailed mechanism and found that TPD52 interacts with p65 subunit of NF-κB that can regulate expression of genes associated with cell growth. From these results, it appears that upon phosphorylation of IkB after being dissociated from IkB, NF-κB p65 interacts with TPD52 in cytoplasm.…”

Pathogenetic Influences of Human Herpesvirus 8 (HHV-8) in Prostate Cancer Progression

“…In addition to being implicated in ligand-independent AR activation and inducing expression of AR-regulated genes (85,86), NF-κB activation, in studies utilizing immunohistochemistry, is found more commonly in prostate cancer lymph node metastases than in localized tumors. In fact, NF-κB activation status in conjunction with…”

“…vFLIP has also been shown to activate the NF-κB (111) and JNK/AP-1 pathways, both of which induce cellular IL-6 expression (113,114). In the context of prostate cancer, increased NF-κB activity and cellular IL-6 signaling have both been shown to be ligandindependent activators of AR expression and transcriptional activity (81,85). Contrary to what we predicted, however, our results suggest that the androgen-independent phenotype induced by HHV-8 in LNCaP cells is independent of the AR signaling pathway.…”