title: Endostatin: A novel inhibitor of androgen receptor function in prostate cancer.
abstract: 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.
authors.affiliation: Departments of Pathology and.
authors.forename: Joo Hyoung
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Departments of Pathology and.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Isayeva
authors.affiliation: Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Larson
authors.affiliation: Departments of Pathology and.
authors.forename: Anandi
authors.initials: A
authors.lastname: Sawant
authors.affiliation: Departments of Pathology and.
authors.forename: Ha-Ram
authors.initials: HR
authors.lastname: Cha
authors.affiliation: Departments of Pathology and.
authors.forename: Diptiman
authors.initials: D
authors.lastname: Chanda
authors.affiliation: Biochemistry and Molecular Genetics, University of Alabama, Birmingham, AL 35294; and.
authors.forename: Igor N
authors.initials: IN
authors.lastname: Chesnokov
authors.affiliation: Departments of Pathology and pons@uab.edu.
authors.forename: Selvarangan
authors.initials: S
authors.lastname: Ponnazhagan
mesh_terms: D000726:Androgen Antagonists / Q000378:metabolism*; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism; D043169:Endostatins / Q000494:pharmacology*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*
chemical_list: D000726:Androgen Antagonists; D043169:Endostatins; D011944:Receptors, Androgen
keywords: androgen receptor; chemoresistance; endostatin; prostate cancer