A Novel Anti-Beta2-Microglobulin Antibody Inhibition of Androgen Receptor Expression, Survival, and Progression in Prostate Cancer Cells
Abstract
Beta2-microglobulin (beta2M) is a signaling and growth-promoting factor stimulating prostate cancer cell proliferation and progression. Blockade of the beta2M signaling axis by anti-beta2M monoclonal antibody (beta2M mAb) 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. 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 beta2M mAb in prostate cancer cells. Furthermore, we revealed a novel molecular mechanism by which SREBP-1 promotes prostate cancer growth, survival 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 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 roles of beta2M and SREBP-1, and their related signaling pathways, including AR, 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 beta2M mAb and SREBP-1 blockers.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2011
- Accession Number
- ADA545571
Entities
People
- Wen-chin Huang
Organizations
- Cedars-Sinai Medical Center