期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：5
页码：1392-1397
DOI：10.1073/pnas.1417660112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceDespite the development of second-generation androgen receptor (AR)-targeted therapies for castration-resistant prostate cancer (CRPC), the effects are only modest, compelling the need for novel therapy combinations that can maximize the antitumor effects of new-generation chemotherapies with minimal acquired resistance, attributed to AR modifications. The present study identified that endostatin (ES), known for its antiangiogenic properties on tumor vasculature, exerts a profound antiproliferative effect on AR-positive human PCa cells. By a systematic approach involving a combination of in situ, cell-free, yeast-two hybrid, structural modeling, and mutagenesis studies, we determined that intracellular trafficking of ES in AR-positive PCa cells leads to a direct interaction with AR in the cytosol, affecting the transcriptional activation of AR target genes. 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 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.
关键词：endostatin ; androgen receptor ; prostate cancer ; chemoresistance
