NF-kappaB Regulation by Androgen Receptor

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DESCRIPTION (provided by applicant): The androgen receptor (AR) is a member of the steroid receptor superfamily of transcription factors. Like other members of the family, AR is regulated primarily through interactions with a specific ligand. Thus androgens bind to AR leading to nuclear translocation, interaction with transcriptional coactivators, and control of gene expression through binding to androgen receptor response elements (AREs) in the promoters of relevant genes to stimulate specific gene expression. Interestingly, androgens have been shown to inhibit gene expression but the mechanisms associated with this process are poorly understood. While there is growing evidence of complex regulation of AR function which occurs independent of androgens, less is known about the ability of AR to affect distinct regulatory pathways that may impact growth or oncogenesis. In this regard, prostate cancer develops as an androgen-dependent cancer. Androgen ablation remains the only effective form of systemic therapy for patients with advanced prostate cancer due to the ineffectiveness of standard forms of cancer therapy. Unfortunately, progression to androgen-independent cancer occurs within a few years of androgen withdrawal and this is associated with extremely poor therapeutic options and with negative prognosis. Because AR-mediated gene activation appears to occur in both androgen-dependent and androgen-independent cancer, it is assumed that aberrant AR responses contribute to the recurrent, androgen-independent tumor. The transcription factor NF-kappaB is considered a key modulator of the immune and inflammatory response through its ability to control expression of genes encoding cytokines, cytokine receptors, and chemokines. Additionally NF-kappaB is a potent inhibitor of apoptosis and can promote cell proliferation through the upregulation of genes such as cyclin D1. Consistent with these points, NF-kappaB is considered a key effector of inflammatory diseases such as arthritis and inflammatory bowel disease. Importantly, NF-kappaB is now recognized as important in a number of cancers including squamous cell carcinoma, breast cancer, and multiple myeloma. The activity of NF-kappaB is controlled at two levels. One mechanism involves interactions with an inhibitory protein known as IkappaB and another mechanism involves direct phosphorylation of the p65 subunit of NF-kappaB which controls transactivation potential. In each case, the IkappaB kinase (IKK) controls the activity of NF-kappaB through its ability to phosphorylate IkappaB, leading to its ubiquitination and degradation, and through its ability to phosphorylate p65 on serine 536. Our preliminary data indicate that androgens potently suppress NF-KB activation through a mechanism which involves inhibition of IkappaBalpha degradation. Additionally, we provide evidence that the phosphorylation of p65 on serine 536, a process associated with IKK and with enhanced transactivation potential, is upregulated in androgen-receptor null cells and in androgen-independent prostate cancer samples. The underlying hypothesis of this proposal is that androgen-activated AR normally functions to suppress NF-kappaB activation through control of IkappaB-alpha degradation and inhibition of phosphorylation of p65. Based on the findings, we also hypothesize that the transition to androgen-independent prostate cancer is associated with a loss of this control on NF-kappaB function, allowing the oncogenic mechanisms associated with NF-kappaB to be manifested. The goals of the application are to determine how androgen activated AR blocks NF-kappaB, with a focus on direct regulation of IKK and on upstream signaling components, and to determine if NF-kappaB is functionally upregulated in androgen-independent prostate cancer. The experiments have the potential to identify a new target in the regulatory cascade associated with androgen/AR signaling and to possibly identify a new target for treatment of androgen-independent cancer.