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

Braadland, Peder Rustøen; Grytli, Helene Hartvedt; Ramberg, Håkon; Katz, Betina; Kellman, Ralf; Gauthier-Landry, Louis; Fazli, Ladan; Krobert, Kurt Allen; Wang, Wanzhong and Levy, Finn Olav, et al. (2015) In Oncotarget
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... (More)
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. (Less)
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Oncotarget
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Impact Journals, LLC
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  • pmid:26646591
  • scopus:84957687315
ISSN
1949-2553
DOI
10.18632/oncotarget.6479
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English
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f14bf0e5-47d9-4257-8722-5cba42b501e6 (old id 8505389)
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http://www.ncbi.nlm.nih.gov/pubmed/26646591?dopt=Abstract
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@article{f14bf0e5-47d9-4257-8722-5cba42b501e6,
  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.},
  author       = {Braadland, Peder Rustøen and Grytli, Helene Hartvedt and Ramberg, Håkon and Katz, Betina and Kellman, Ralf and Gauthier-Landry, Louis and Fazli, Ladan and Krobert, Kurt Allen and Wang, Wanzhong and Levy, Finn Olav and Bjartell, Anders and Berge, Viktor and Rennie, Paul S and Mellgren, Gunnar and Mælandsmo, Gunhild Mari and Svindland, Aud and Barbier, Olivier and Taskén, Kristin Austlid},
  issn         = {1949-2553},
  language     = {eng},
  month        = {12},
  publisher    = {Impact Journals, LLC},
  series       = {Oncotarget},
  title        = {Low β2-adrenergic receptor level may promote development of castration resistant prostate cancer and altered steroid metabolism.},
  url          = {http://dx.doi.org/10.18632/oncotarget.6479},
  year         = {2015},
}