Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 5, Pages 1392-1397Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1417660112
Keywords
endostatin; androgen receptor; prostate cancer; chemoresistance
Categories
Funding
- National Institutes of Health [CA132077, CA133737, GM97052]
- Department of Defense [DoD-BC101411]
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Acquired resistance to androgen receptor (AR)-targeted therapies compels the development of novel treatment strategies for castration- resistant prostate cancer (CRPC). Here, we report a profound effect of endostatin on prostate cancer cells by efficient intracellular trafficking, direct interaction with AR, reduction of nuclear AR level, and down-regulation of AR-target gene transcription. Structural modeling followed by functional analyses further revealed that phenylalanine-rich alpha 1-helix in endostatin-which shares structural similarity with noncanonical nuclear receptor box in AR-antagonizes AR transcriptional activity by occupying the activation function (AF)-2 binding interface for coactivators and N-terminal AR AF-1. Together, our data suggest that endostatin can be recognized as an endogenous AR inhibitor that impairs receptor function through protein-protein interaction. These findings provide new insights into endostatin whose antitumor effect is not limited to inhibiting angiogenesis, but can be translated to suppressing AR-mediated disease progression in CRPC.
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