β2-Microglobulin antibody inhibition of androgen receptor expression and survival in prostate cancer

Abstract

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We previously reported that β2-microglobulin (β2M) promoted osteomimicry and cell proliferation through a cAMP-dependent protein kinase A (PKA) signaling pathway in human prostate cancer cells. Targeting β2M and its signaling axis using β2M siRNA induced apoptotic death of prostate cancer cells in vitro and in vivo as subcutaneous and bone tumor xenografts (Huang, et al. Cancer Res. 65:2303-13, 2005; and 66:9108-16, 2006). In this presentation, we utilized anti-β2M antibody (β2M Ab) as a new approach to block the β2M signaling and observed the effect on expression of the androgen receptor (AR) and its target gene, prostate-specific antigen (PSA), and cell growth and survival in prostate cancer cells. Treatment of AR- and PSA-positive prostate cancer cell lines, LNCaP (androgen-dependent) and its lineage-related C4-2B (androgen-independent) cells with β2M Ab resulted in a dose-dependent inhibition of AR and PSA mRNA and protein expression determined by RT-PCR and Western blot; this inhibitory effect was attenuated by purified β2M protein. We further demonstrated that the decrease of AR and PSA expression mediated by β2M Ab was through down-regulation of phosphorylated extracellular signal-regulated kinase (ERK, p44/p42) and a nuclear transcription factor, sterol regulatory element binding protein-1 (SREBP-1). β2M Ab also showed to induce prostate cancer cell programmed death as indicated by activation of apoptotic markers, cleaved caspase-9, caspase-3 and PARP, and inhibition of survivin expression. β2M Ab, however, exhibited low toxicity in normal human prostate epithelial and stromal cells. β2M Ab, when administered to mice bearing prostate tumors, was shown to decrease greatly AR and induce marked prostate tumor death as demonstrated by immunohistochemical analysis and M30 CytoDeath marker staining compared to the control groups. These exciting findings suggested that interrupting β2M and its signaling axis by using a novel β2M Ab may provide a promising and safe therapeutic approach for the treatment of human prostate cancer and its progression.