Low β2-adrenergic receptor level may promote development of castration resistant prostate cancer and altered steroid metabolism

// Peder Rustøen Braadland 1,* , Helene Hartvedt Grytli 1,* , Håkon Ramberg 1,* , Betina Katz 2 , Ralf Kellman 3 , Louis Gauthier-Landry 4 , Ladan Fazli 5 , Kurt Allen Krobert 6,7 , Wanzhong Wang 8 , Finn Olav Levy 6,7 , Anders Bjartell 9,10 , Viktor Berge 11 , Paul S. Rennie 5 , Gunnar Mellgren 3,12 , Gunhild Mari Mælandsmo 1,13 , Aud Svindland 2,14 , Olivier Barbier 4 and Kristin Austlid Taskén 1,14 1 Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway 2 Department of Pathology, Oslo University Hospital, Oslo, Norway 3 Hormone Laboratory, Haukeland University Hospital, Bergen, Norway 4 Laboratory of Molecular Pharmacology, CHU-Québec Research Center and Faculty of Pharmacy, Laval University, Québec, Canada 5 The Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada 6 Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway 7 K.G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway 8 Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden 9 Department of Urology, Skåne University Hospital, Malmø, Sweden 10 Department of Clinical Sciences Malmø, Division of Urological Cancers, Lund University, Lund, Sweden 11 Department of Urology, Oslo University Hospital, Oslo, Norway 12 Department of Clinical Science, University of Bergen, Bergen, Norway 13 Institute for Pharmacy, Faculty of Health Science, University of Tromsø, Tromsø, Norway 14 Institute of Clinical Medicine, University of Oslo, Oslo, Norway * These authors have contributed equally to this work Correspondence to: Kristin Austlid Taskén, email: // Keywords : β2-adrenergic receptor, ADRB2, CRPC, UGT2B15, UGT2B17 Received : June 02, 2015 Accepted : November 21, 2015 Published : December 05, 2015 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 β 2 -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.