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Endostatin: A novel inhibitor of androgen receptor function in prostate cancer

Significance Despite 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 α1-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.