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.
Highlights
Androgen deprivation therapy (ADT) is the first line of treatment for patients with advanced or metastatic prostate cancer [1]
Kaplan-Meier plots showing time to castration resistant prostate cancers (CRPC) development and prostate cancer- specific mortality in patients stratified according to staining intensity above and below mean are shown in Figure 1c and 1d
Competing risk regression modelling showed that increasing staining intensity was associated with increased time to CRPC development, with an adjusted SHR of 0.67 (Table 1)
Summary
Androgen deprivation therapy (ADT) is the first line of treatment for patients with advanced or metastatic prostate cancer [1]. The multiple molecular mechanisms by which the androgen receptor (AR) contributes to disease progression despite castration levels of androgens in prostate cancer have been thoroughly reviewed [3,4,5,6]. Several new targets in the AR activation pathway have emerged in recent years [7, 8]. The steroidogenic pathway has received increasing attention, as drugs targeting this pathway, such as abiraterone (an inhibitor of cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17)) improve the life expectancy of patients with CRPC, despite the assumed androgen-independence of these cancer cases [8]. Targeting the androgen extrahepatic phase-II metabolic pathways has arisen as a potential tool to help maintain androgen-deprived conditions during ADT [9]. The UDPglucuronosyltransferases 2B15 (UGT2B15) and 2B17 (UGT2B17) are of special interest, as they are expressed in prostate tissue and cell lines, and they exhibit specificity for androgen metabolites [10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
