Androgen Glucuronidation: An Unexpected Target for Androgen Deprivation Therapy, with Prognosis and Diagnostic Implications

Abstract

Androgen deprivation therapy (ADTh) remains a mainstay of prostate cancer treatment, but its efficacy is bypassed by mechanisms that are not fully understood. In human prostate cancer cells, androgen glucuronidation, catalyzed by the two UDP-glucuronosyltransferase (UGT) enzymes UGT2B15 and UGT2B17, is the major androgen inactivation pathway. In this study, we investigated the effect of ADTh on androgen glucuronidation to evaluate its potential clinical utility for prostate cancer prognosis or therapy. UGT2B15 and UGT2B17 expression was evaluated in prostate cancer specimens from untreated or treated patients and in cell models of prostate cancer exposed to clinically relevant antiandrogens. UGT2B15 and UGT2B17 protein levels in prostate were increased after 5 months of ADTh when compared with specimens from untreated patients. UGT2B15 expression remained elevated for up to 12 months, but UGT2B17 returned to initial levels as soon as after 6 months. Several androgen receptor (AR) antagonists tested caused a dose-and time-dependent stimulation of UGT2B15 and UGT2B17 expression and androgen glucuronidation in prostate cancer cell lines. The role of AR in these regulatory events was confirmed using AR-deficient LNCaP cells, in which UGT2B attenuation reduced the antiproliferative effects of AR pharmacologic antagonists. Through this combination of clinical and functional investigations, our work revealed that ADTh stimulates a local androgen metabolism in prostate cells, establishing a foundation to evaluate the potential of UGT2B15 and UGT2B17 as drug targets and/or molecular markers for ADTh responsiveness and maintenance in prostate cancer. Cancer Res; 73(23); 6963-71. Ó2013 AACR.

DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis

“…Similar regulation of other UGT enzymes after DNA-PKcs depletion (Fig 3B) argues against functional redundancy impacting DHT levels. The overall findings are of translational significance, as UGT2B15 and 2B17 are being developed as prognostic markers and therapeutic targets in PCa (Grosse et al, 2013), and the mechanisms of regulation are not well understood. To assess clinical relevance, a cohort of 232 patients with high-risk localized PCa was examined, wherein it was observed that both UGT2B15 (correlation coefficient −0.28, p<0.0001) and UGT2B17 (correlation coefficient −0.38, p<0.0001) expression strongly negatively correlated with DNA-PKcs (Fig 3H), supporting the concept that DNA-PKcs suppresses expression of UGT enzymes in human tumors.…”

“…Factors influencing UGT expression in non-prostatic tissues include NRF and Sp1 (Mackenzie et al, 2010), and influence on these factors may contribute to the impact of DNA-PKcs. Since UGT2B15 and 2B17 are being evaluated as pharmacologic targets for PCa management (Grosse et al, 2013), the identified link to DNA-PKcs may prove important in designing therapeutic regimens.…”

Nuclear Receptor Corepressor 1 Expression and Output Declines with Prostate Cancer Progression

“…They stimulate androgen removal and are implicated in PCa (27). UGT2B15 and UGT2B17 are directly repressed by AR in an agonist-dependent manner (28).…”

Targeting Androgen Receptor Action for Prostate Cancer Treatment: Does the Post-Receptor Level Provide Novel Opportunities?

“…Because of these and related findings, yet other means to target AR for CaP treatment are being explored. Such efforts are directed for instance at identifying and exploiting the differences in the AR protein interactome that is associated with wild-type or mutant AR, development of novel agents that interfere with the ligand-independent activity of AR 52,53, modulation of the degradation rather than synthesis of intratumoral androgens 54, or combined administration of an AR antagonist and an GR antagonist 49. In the era of precision medicine, it has been proposed to tailor administration of these treatments based on a CaP's expression status of (mutant) AR, pattern of expression or structural integrity of steroidogenic enzymes.…”