title: Low β₂-adrenergic receptor level may promote development of castration resistant prostate cancer and altered steroid metabolism.
abstract: The underlying mechanisms responsible for the development of castration-resistant prostate cancer (CRPC) in patients who have undergone androgen deprivation therapy are not fully understood. This is the first study to address whether β2-adrenergic receptor (ADRB2)- mediated signaling may affect CRPC progression in vivo. By immunohistochemical analyses, we observed that low levels of ADRB2 is associated with a more rapid development of CRPC in a Norwegian patient cohort. To elucidate mechanisms by which ADRB2 may affect CRPC development, we stably transfected LNCaP cells with shRNAs to mimic low and high expression of ADRB2. Two UDP-glucuronosyltransferases, UGT2B15 and UGT2B17, involved in phase II metabolism of androgens, were strongly downregulated in two LNCaP shADRB2 cell lines. The low-ADRB2 LNCaP cell lines displayed lowered glucuronidation activities towards androgens than high-ADRB2 cells. Furthermore, increased levels of testosterone and enhanced androgen responsiveness were observed in LNCaP cells expressing low level of ADRB2. Interestingly, these cells grew faster than high-ADRB2 LNCaP cells, and sustained their low glucuronidation activity in castrated NOD/SCID mice. ADRB2 immunohistochemical staining intensity correlated with UGT2B15 staining intensity in independent TMA studies and with UGT2B17 in one TMA study. Similar to ADRB2, we show that low levels of UGT2B15 are associated with a more rapid CRPC progression. We propose a novel mechanism by which ADRB2 may affect the development of CRPC through downregulation of UGT2B15 and UGT2B17.
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Peder Rustøen
authors.initials: PR
authors.lastname: Braadland
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Helene Hartvedt
authors.initials: HH
authors.lastname: Grytli
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Håkon
authors.initials: H
authors.lastname: Ramberg
authors.affiliation: Department of Pathology, Oslo University Hospital, Oslo, Norway.
authors.forename: Betina
authors.initials: B
authors.lastname: Katz
authors.affiliation: Hormone Laboratory, Haukeland University Hospital, Bergen, Norway.
authors.forename: Ralf
authors.initials: R
authors.lastname: Kellman
authors.affiliation: Laboratory of Molecular Pharmacology, CHU-Québec Research Center and Faculty of Pharmacy, Laval University, Québec, Canada.
authors.forename: Louis
authors.initials: L
authors.lastname: Gauthier-Landry
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada.
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.affiliation: Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway.|K.G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Kurt Allen
authors.initials: KA
authors.lastname: Krobert
authors.affiliation: Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
authors.forename: Wanzhong
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway.|K.G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Finn Olav
authors.initials: FO
authors.lastname: Levy
authors.affiliation: Department of Urology, Skåne University Hospital, Malmø, Sweden.|Department of Clinical Sciences Malmø, Division of Urological Cancers, Lund University, Lund, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Bjartell
authors.affiliation: Department of Urology, Oslo University Hospital, Oslo, Norway.
authors.forename: Viktor
authors.initials: V
authors.lastname: Berge
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Rennie
authors.affiliation: Hormone Laboratory, Haukeland University Hospital, Bergen, Norway.|Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Mellgren
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.|Institute for Pharmacy, Faculty of Health Science, University of Tromsø, Tromsø, Norway.
authors.forename: Gunhild Mari
authors.initials: GM
authors.lastname: Mælandsmo
authors.affiliation: Department of Pathology, Oslo University Hospital, Oslo, Norway.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Aud
authors.initials: A
authors.lastname: Svindland
authors.affiliation: Laboratory of Molecular Pharmacology, CHU-Québec Research Center and Faculty of Pharmacy, Laval University, Québec, Canada.
authors.forename: Olivier
authors.initials: O
authors.lastname: Barbier
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Kristin Austlid
authors.initials: KA
authors.lastname: Taskén
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000097:blood*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C553443:ADRB2 protein, human; D000726:Androgen Antagonists; D000728:Androgens; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018343:Receptors, Adrenergic, beta-2; D014453:Glucuronosyltransferase; C472000:UDP-glucuronosyltransferase 2B15, human; C500513:UGT2B17 protein, human
keywords: ADRB2; CRPC; UGT2B15; UGT2B17; β2-adrenergic receptor