title: Maintenance of androgen receptor inactivation by S-nitrosylation.
abstract: Antiandrogens target ligand-binding domain of androgen receptor (AR) and are used as first-line therapeutics to treat patients diagnosed with locally advanced and metastatic prostate cancer. Although initially beneficial as judged with actual tumor mass shrinkage, this therapy invariably fails and the cancer reappears as castration-resistant disease. Here, we report that increased intracellular nitric oxide (NO) levels lead to growth inhibition of both androgen-dependent and castration-resistant prostate tumors through a mechanism that involves AR function inactivation by S-nitrosylation of a single C601 residue present in the DNA-binding domain. AR S-nitrosylation does not impact its subcellular distribution but attenuates its ability to bind AR-responsive elements in promoter region of target genes. Mechanistically, AR is transnitrosylated by its partner HSP90 protein. Ubiquitous small-molecule NO donors promote the AR S-nitrosylation and inhibit growth of castration-resistant prostate tumors. These findings reveal a new mechanism of regulating AR function and suggest that sequential targeting of distinct domains of AR may extend therapeutic efficacy for patients with advanced prostate cancer.
authors.affiliation: Authors' Affiliation: Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, Florida.
authors.forename: Yu
authors.initials: Y
authors.lastname: Qin
authors.forename: Anindya
authors.initials: A
authors.lastname: Dey
authors.forename: Hamsa Thayele
authors.initials: HT
authors.lastname: Purayil
authors.forename: Yehia
authors.initials: Y
authors.lastname: Daaka
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009569:Nitric Oxide / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011944:Receptors, Androgen / Q000378:metabolism*; D026403:S-Nitrosothiols / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D011944:Receptors, Androgen; D026403:S-Nitrosothiols; D013438:Sulfhydryl Compounds; D009569:Nitric Oxide