title: Partial agonist/antagonist properties of androstenedione and 4-androsten-3beta,17beta-diol.
abstract: Androgens play important endocrine roles in development and physiology. Here, we characterize activities of two "Andro" prohormones, androstenedione (A-dione) and 4-androsten-3beta,17beta-diol (A-diol) in MDA-MB-453 (MDA) and LNCaP cells. A-dione and A-diol, like cyproterone acetate, were partial agonists of transfected mouse mammary tumor virus (MMTV) and endogenous prostate-specific antigen (PSA) promoters. Different from bicalutamide but similar to CPA, both are inducers of LNCaP cell proliferation with only mild suppression of 5alpha-dihydrotestosterone (DHT)-enhanced cell growth. Like bicalutamide and cyproterone acetate, A-dione and A-diol significantly antagonized DHT/R1881-induced PSA expression by up to 30% in LNCaP cells. Meanwhile, in MDA cells, EC(50)s for the MMTV promoter were between 10 and 100nM. Co-factor studies showed GRIP1 as most active for endogenous androgen receptor (AR), increasing MMTV transcription by up to five-fold, without substantially altering EC(50)s of DHT, A-dione or A-diol. Consistent with their transcriptional activities, A-dione and A-diol bound full-length endogenous AR from MDA or LNCaP cells with affinities of 30-70nM, although binding to expressed ligand-binding domain (LBD) was >20-fold weaker. In contrast, DHT, R1881, and bicalutamide bound similarly to LBD or aporeceptor. Together, these data suggest that A-dione and A-diol are ligands for AR with partial agonist/antagonist activities in cell-based transcription assays. Binding affinities for both are most accurately assessed by AR aporeceptor complex. In addition to being testosterone precursors in vivo, either may impart its own transcriptional regulation of AR.
authors.affiliation: Department of Molecular Endocrinology, Merck Research Laboratory, WP26A-1000, Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: F
authors.initials: F
authors.lastname: Chen
authors.forename: K
authors.initials: K
authors.lastname: Knecht
authors.forename: C
authors.initials: C
authors.lastname: Leu
authors.forename: S J
authors.initials: SJ
authors.lastname: Rutledge
authors.forename: A
authors.initials: A
authors.lastname: Scafonas
authors.forename: C
authors.initials: C
authors.lastname: Gambone
authors.forename: R
authors.initials: R
authors.lastname: Vogel
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: V
authors.initials: V
authors.lastname: Kasparcova
authors.forename: C
authors.initials: C
authors.lastname: Bai
authors.forename: S
authors.initials: S
authors.lastname: Harada
authors.forename: A
authors.initials: A
authors.lastname: Schmidt
authors.forename: A
authors.initials: A
authors.lastname: Reszka
authors.forename: L
authors.initials: L
authors.lastname: Freedman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000726:Androgen Antagonists / Q000494:pharmacology; D059002:Androgen Receptor Antagonists; D000728:Androgens / Q000494:pharmacology; D015114:Androstenediol / Q000494:pharmacology*; D000735:Androstenedione / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002522:Chlorocebus aethiops; D017373:Cyproterone Acetate / Q000494:pharmacology; D013196:Dihydrotestosterone / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008253:Macaca mulatta / Q000235:genetics; D008297:Male; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009570:Nitriles; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017430:Prostate-Specific Antigen / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D018091:Receptors, AMPA / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics; D014105:Tosyl Compounds; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000728:Androgens; D000813:Anilides; D002352:Carrier Proteins; C491310:GRIP1 protein, human; C491309:Grip1 protein, mouse; D008024:Ligands; D009419:Nerve Tissue Proteins; D009570:Nitriles; D018091:Receptors, AMPA; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D013196:Dihydrotestosterone; D000735:Androstenedione; D017373:Cyproterone Acetate; D015114:Androstenediol; C053541:bicalutamide; D017430:Prostate-Specific Antigen