Abstract
Castration-resistant prostate cancer (CRPC) is characterized by a shift in androgen receptor (AR) signaling from androgen-dependent to androgen (ligand)-independent. UDP-glucuronosyltransferase 2B17 (UGT2B17) is a key enzyme that maintains androgen homeostasis by catabolizing AR agonists into inactive forms. Although enhanced UGT2B17 expression by antiandrogens has been reported in androgen-dependent prostate cancer, its roles in regulating AR signaling transformation and CRPC progression remain unknown. In this study, we show that higher UGT2B17 protein expression in prostate tumors is associated with higher Gleason score, metastasis, and CRPC progression. UGT2B17 expression and activity were higher in androgen-independent compared to androgen-dependent cell lines. UGT2B17 stimulated cancer cell proliferation, invasion, and xenograft progression to CRPC after prolonged androgen deprivation. Gene microarray analysis indicated that UGT2B17 suppressed androgen-dependent AR transcriptional activity and enhanced of ligand-independent transcriptional activity at genes associated with cell mitosis. These UGT2B17 actions were mainly mediated by activation of the c-Src kinase. In CRPC tumors, UGT2B17 expression was associated positively with c-Src activation. These results indicate that UGT2B17 expedites CRPC progression by enhancing ligand-independent AR signaling to activate cell mitosis in cancer cells. Cancer Res; 76(22); 6701-11. ©2016 AACR.
Highlights
Androgen receptor (AR) signaling is critical for prostate cancer development as well as progression into castrationresistant prostate cancer (CRPC; refs. 1, 2)
Our studies identify a novel function for UDP-glucuronosyltransferase 2B17 (UGT2B17) that promotes ligand-independent AR signaling to expedite CRPC progression
We demonstrate that elevated UGT2B17, under conditions of prolonged androgen deprivation, activates c-Src kinase and stimulates AR transactivation independent of androgens (Fig. 6B)
Summary
Androgen receptor (AR) signaling is critical for prostate cancer development as well as progression into castrationresistant prostate cancer (CRPC; refs. 1, 2). Several possible mechanisms that restore AR signaling have been defined, including AR gene overexpression and amplification [5], AR gain-of-function mutations in the LBD with a more promiscuous affinity to other ligands [6], aberrant AR gene splicing encoding constitutively active forms of AR [7, 8], and phosphorylation and subsequent activation of AR in the absence of androgen [9] These findings indicate that AR LBD inhibitors are insufficient to abolish AR signaling and that tumor cells can use ligand-independent AR signaling to enable progression under anti-AR therapies. This notion is further supported by genome-wide studies showing that AR remains
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