Novel Anti-Beta2-Microglobulin Antibody Inhibition of Androgen Receptor Expression, Survival, and Progression in Prostate Cancer Cells.

摘要

Beta 2-microglobulin ( 2M) is a signaling and growth-promoting factor stimulating prostate cancer cell proliferation and progression. Blockade of the Beta 2M signaling axis resulted in the inhibition of androgen receptor (AR) and its target gene, prostate-specific antigen (PSA), and the induction of programmed death of prostate cancer cells in vitro and in vivo. Also, we identified a new cis-acting element, sterol regulatory element-binding protein- 1 (SREBP-1) binding site, within the 5 -flanking human AR promoter region and its binding transcription factor, SREBP-1, regulating AR transcription by anti- Beta 2M monoclonal antibody in prostate cancer cells. Furthermore, we revealed the novel molecular mechanism by which SREBP-1 promotes prostate cancer growth and progression. Alteration of SREBP-1 expression leads to regulate AR expression, cell growth, migration and invasion in prostate cancer cells. SREBP- 1 also showed to induce fatty acid and lipid formation in prostate cancer cells through increase of fatty acid synthase expression. Additionally, SREBP-1 induced oxidative stress and NADPH oxidase 5 (Nox5) expression in prostate cancer cells. In subcutaneous xenograft mouse models, SREBP-1 significantly increased LNCaP tumor growth and promoted prostate tumor castration-resistant progression. These findings provided a new concept to reveal the role of Beta 2M and its related signaling pathways, including AR, SREBP-1, fat metabolism and oxidative stress, contribute to prostate cancer growth, survival and progression, and further provides a new potential target to prevent and treat prostate cancer malignancy by using anti-Beta 2M monoclonal antibody.