Androgen Receptor Survival Signaling Is Blocked by Anti-β2-microglobulin Monoclonal Antibody via a MAPK/Lipogenic Pathway in Human Prostate Cancer Cells

Abstract

A new cis-acting element, sterol regulatory element-binding protein-1 (SREBP-1) binding site, within the 5-flanking human androgen receptor (AR) promoter region and its binding transcription factor, SREBP-1, was identified to regulate AR transcription in AR-positive human prostate cancer cells. We further characterized the molecular mechanism by which a novel anti-␤2-microglobulin monoclonal antibody (␤2M mAb), shown to induce massive cell death in a number of human and mouse cancer cell lines, interrupted multiple cell signaling pathways in human prostate cancer cells. ␤2M mAb decreased AR expression through inactivation of MAPK and SREBP-1. By inactivation of MAPK, ␤2M mAb decreased prostate cancer cell proliferation and survival. By inhibition of SREBP-1, ␤2M mAb reduced fatty acid and lipid levels, an integral component of cell membrane, cell signaling mediators, and energy metabolism. These results provide for the first time a molecular link between the ␤2M intracellular signaling axis mediated by MAPK and SREBP-1 and involving lipid signaling, which collectively regulates AR expression and function. Antagonizing ␤2M by ␤2M mAb may be an effective therapeutic approach simultaneously targeting multiple downstream signaling pathways converging with MAPK, SREBP-1, and AR, important for controlling prostate cancer cell growth, survival, and progression. ␤2-Microglobulin (␤2M)3 is a co-receptor of a major histocompatibility complex class I antigen. ␤2M has been implicated in the regulation of the host immune mechanism and is essential for the recognition of foreign antigens by T-lymphocytes (1). Recent reports from our laboratory and others assigned additional biological functions to ␤2M as a diagnostic and prognostic indicator for multiple myeloma, prostate, and breast cancers (2-5); a growth factor and a signaling molecule (6, 7); a new androgen and androgen receptor (AR) target gene (8); and an attractive new therapeutic target for both liquid (9) and solid (10, 11) tumor malignancies. Blockade of ␤2M and its related signaling pathways by sequence-specific siRNA or antibody resulted in the inhibition of AR expression and activity and the induction of extensive prostate cancer cell death in vitro as well as prostate tumor regression in immune-compromised mice (7, 10). In addition, anti-␤2M monoclonal antibody (␤2M mAb) has been shown not to significantly affect the growth of normal cells, consistent with experimental observations where transgenic mice with a ␤2M deficit had normal organ function and life expectancy (9, 10, 12). Therefore, ␤2M and its signaling axis may offer an opportunity for improving the clinical targeting of prostate cancer.AR is a key growth and survival regulatory transcription factor for androgen target organs during normal development and neoplastic progression. Recognition of the importance of the AR signaling axis, particularly in castration-resistant prostate cancer, has prompted discoveries targeting androgen biosynthetic pathways using abiraterone as an agent for a Phase III trial...

Pro-survival and anti-apoptotic properties of androgen receptor signaling by oxidative stress promote treatment resistance in prostate cancer

“…As we summarized previously (Shiota et al 2011b (Mizokami et al 1994), and Foxo3a (Yang et al 2005), regulate AR expression. In addition, it has recently been shown that the SREBP-1 transcription factor regulates AR expression (Huang et al 2010), is overexpressed during progression to castration resistance (Ettinger et al 2004), regulates lipogenesis, and induces oxidative stress via NADPH oxidase 5 (Nox5) expression that can be reversed by the Nox inhibitor diphenyliodonium (DPI). Intriguingly, AR expression was shown to be repressed by DPI, indicating that AR expression by SREBP-1 may be mediated by the Nox pathway .…”

Androgen control of lipid metabolism in prostate cancer: novel insights and future applications

“…SREBPs can reciprocally activate the expression of AR via binding to an SRE in the 5′-untranslated region of the AR gene (Fig. 2) (Huang et al 2010), and modulation of SREPB1 activity has parallel effects on AR expression and function (Fig. 2) .…”

Differential protein analysis of chicken skin infected with Marek΄s disease virus

“…Recent studies have demonstrated that tumor cells treated with antibodies specific for β2M or MHC class I molecules undergo apoptosis in vitro and in vivo (in a mouse model). These findings suggest that targeting of either β2M or MHC class I offers a potential therapeutic approach for the treatment of β2M/MHC class I-expressing malignancies (Cao et al, 2011;Huang et al, 2010;Shi et al, 2009;Triozzi et al, 2013;Yang and Yi, 2010). However, the specific function of β2M in modulating tumorigenesis is poorly understood.…”