IκB Kinases Modulate the Activity of the Androgen Receptor in Prostate Carcinoma Cell Lines

Abstract

Enhanced nuclear localization of nuclear factor κB (NF-κB) in prostate cancer (PCa) samples and constitutive NF-κB signaling in a class of PCa cell lines with low androgen receptor (AR) expression (PC3 and DU-145) imply an important role of the IκB kinase (IKK)/NF-κB system in PCa. However, most PCa and PCa cell lines depend on the activity of the AR, and the role of NF-κB in these AR-expressing PCa remains unclear. Here, we demonstrate that inhibition of NF-κB signaling by the IKK inhibitor BMS345541 reduced proliferation and increased apoptosis in AR-expressing PCa cell lines. Furthermore, AR activity and target gene expression were distinctively reduced, whereas AR protein levels remained unaltered on BMS345541 treatment. Similar effects were observed particularly after small interfering RNA (siRNA)-mediated knockdown of IKK1, but not by siRNA-mediated suppression of IKK2. Moreover, IKK1 overexpression augmented 5α-dihydrotestosterone-induced nuclear AR translocation, whereas nuclear AR was reduced by IKK1 knockdown or BMS345541. However, because IKK1 also enhances the activity of a chronically nuclear AR mutant, modulation of the subcellular distribution seems not to be the only mechanism by which IKK1 enhances AR activity. Finally, reduced in vivo AR phosphorylation after BMS345541 treatment and in vitro AR phosphorylation by IKK1 or IKK2 imply that AR constitutes a novel IKK target. Taken together, our data identify IKK1 as a potentially target structure for future therapeutic intervention in PCa.

Regulation of the androgen receptor by post-translational modifications

“…IKK and IKK2 have recently been shown to phosphorylate the AR in vitro, consistent with the IKK inhibitor BMS345541 being able to reduce AR-P in vivo (Jain et al 2012), indicating crosstalk with yet another pathway and further demonstrating the increasing complexity of AR signalling.…”

Proteasome Inhibition by Bortezomib Increases IL-8 Expression in Androgen-Independent Prostate Cancer Cells: The Role of IKKα

“…While no activated IKKα was detected in nuclear fractions of normal human prostate or benign prostate hyperplasia, stage 4 tumors exhibited the highest nuclear levels and activity of IKKα (64). Furthermore, a recent study showed that IKKα regulates expression of androgen receptor in prostate cancer cells (65). …”

Recent insights into NF‐κB signalling pathways and the link between inflammation and prostate cancer

“…Another IKK‐inhibitor, BMS345541, was shown to reduce proliferation in AR‐expressing PCa cell lines. This effect was accompanied by a reduction in AR activity . To date, however, none of these agents has received clinical approval and further development is warranted.…”