title: Inhibition of Stat5a/b Enhances Proteasomal Degradation of Androgen Receptor Liganded by Antiandrogens in Prostate Cancer.
abstract: Although poorly understood, androgen receptor (AR) signaling is sustained despite treatment of prostate cancer with antiandrogens and potentially underlies development of incurable castrate-resistant prostate cancer. However, therapies targeting the AR signaling axis eventually fail when prostate cancer progresses to the castrate-resistant stage. Stat5a/b, a candidate therapeutic target protein in prostate cancer, synergizes with AR to reciprocally enhance the signaling of both proteins. In this work, we demonstrate that Stat5a/b sequesters antiandrogen-liganded (MDV3100, bicalutamide, flutamide) AR in prostate cancer cells and protects it against proteasomal degradation in prostate cancer. Active Stat5a/b increased nuclear levels of both unliganded and antiandrogen-liganded AR, as demonstrated in prostate cancer cell lines, xenograft tumors, and clinical patient-derived prostate cancer samples. Physical interaction between Stat5a/b and AR in prostate cancer cells was mediated by the DNA-binding domain of Stat5a/b and the N-terminal domain of AR. Moreover, active Stat5a/b increased AR occupancy of the prostate-specific antigen promoter and AR-regulated gene expression in prostate cancer cells. Mechanistically, both Stat5a/b genetic knockdown and antiandrogen treatment induced proteasomal degradation of AR in prostate cancer cells, with combined inhibition of Stat5a/b and AR leading to maximal loss of AR protein and prostate cancer cell viability. Our results indicate that therapeutic targeting of AR in prostate cancer using antiandrogens may be substantially improved by targeting of Stat5a/b.
authors.affiliation: Deparment of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: David T
authors.initials: DT
authors.lastname: Hoang
authors.affiliation: Deparment of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Lei
authors.initials: L
authors.lastname: Gu
authors.affiliation: Deparment of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Liao
authors.affiliation: Deparment of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Feng
authors.initials: F
authors.lastname: Shen
authors.affiliation: Deparment of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Pooja G
authors.initials: PG
authors.lastname: Talati
authors.affiliation: Deparment of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Koptyra
authors.affiliation: Deparment of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Shyh-Han
authors.initials: SH
authors.lastname: Tan
authors.affiliation: Deparment of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Elyse
authors.initials: E
authors.lastname: Ellsworth
authors.affiliation: Deparment of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Medical Oncology, H. Lee Moffit Cancer Center and Research Institute, University of South Florida, Tampa, Florida.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Heather
authors.initials: H
authors.lastname: Montie
authors.affiliation: Deparment of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Ayush
authors.initials: A
authors.lastname: Dagvadorj
authors.affiliation: Deparment of Physiology, University of Turku, Turku, Finland. Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.
authors.forename: Saija
authors.initials: S
authors.lastname: Savolainen
authors.affiliation: Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Leiby
authors.affiliation: Deparment of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Pathology, Haartman Institute, University of Helsinki and HUSLAB, Helsinki, Finland. Finnish Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: Tuomas
authors.initials: T
authors.lastname: Mirtti
authors.affiliation: Department of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Merry
authors.affiliation: Deparment of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. marja.nevalainen@jefferson.edu.
authors.forename: Marja T
authors.initials: MT
authors.lastname: Nevalainen
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology; D001549:Benzamides; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D005485:Flutamide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008024:Ligands; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D017430:Prostate-Specific Antigen / Q000235:genetics; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014105:Tosyl Compounds / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors*
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; D001549:Benzamides; D008024:Ligands; D009570:Nitriles; D011944:Receptors, Androgen; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; D014105:Tosyl Compounds; D025521:Tumor Suppressor Proteins; D010669:Phenylthiohydantoin; D005485:Flutamide; C540278:enzalutamide; C053541:bicalutamide; D017430:Prostate-Specific Antigen; D046988:Proteasome Endopeptidase Complex