Development of castration-resistant prostate cancer: The role of androgen glucuronidation

Prostate cancer cells express phase II-metabolism enzymes involved in glucuronidation of androgens. These enzymes, termed uridine diphosphate-glucuronosyltransferases 2B (UGT2B’s), transfer glucuronosyl groups from uridine diphosphate glucuronic acid (UDPGA) to i.e. androgens, increasing their water solubility. Androgens such as DHT, androstane-3α,17b-diol (3α-Diol) and androsterone (ADT) can be glucuronated by UGT2B15 and 2B17, and the reaction is locally irreversible. In prostate cancer, these two enzymes are getting elevated attention, as they exert enzymatic activity towards androgens, which activate the AR signalling axis. Androgen glucuronides are biologically inactive.

Lately, UGT2B15 and UGT2B17 have been shown to not only alter the risk of developing prostate cancer, but to also play a role in the disease progression.The β2-adrenergic receptor (ADRB2) and its downstream effector cAMP have been implicated in androgen receptor (AR) signalling. Previous immunological studies have shown a positive correlation between the level of ADRB2 and time to biochemical recurrence. Expressional analyses of LNCaP cells stably transfected with shRNA targeting ADRB2 showed markedly reduced levels of UGT2B15 and UGT2B17. In this study we investigate the functional effects of ADRB2 knockdown on androgen glucuronidation, and couple it to findings from immunohistochemical staining of prostate cancer specimens. The studies may shed light on the processes contributing to ADRB2 as a prognostic marker in prostate cancer.

The findings were published December 2015: Low β₂-adrenergic receptor level may promote development of castration resistant prostate cancer and altered steroid metabolism.

Group members who work on this project: Håkon Ramberg (Institute for Cancer Research, Oslo University Hospital), Peder Rustøen Braadland (Institute for Cancer Research, Oslo University Hospital)