Abstract 1576: UGT2B17 promotes castration-resistant prostate cancer progression through enhancing ligand-independent AR signaling
Bibliographic record
Abstract
Abstract Background: Castration resistant prostate cancer (CRPC) is characterized by a shift of androgen receptor (AR) signaling from ligand-dependent to ligand-independent. Defining mechanisms that control AR signaling transformation is important to develop therapies for disease control. 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 was reported in androgen-independent prostate cancers, its role in regulating AR signaling transformation and CRPC progression remain unknown. Method and Results: We first evaluated the UGT2B17 protein expression levels by immunohistochemistry (IHC) on Vancouver Prostate Centre tissue microarrays. We show that higher UGT2B17 protein expression in prostate tumors is associated with higher Gleason score, metastasis and CRPC progression. The expression and activity of UGT2B17 are also higher in androgen-independent compared to androgen-dependent cell lines. Interestingly, enzalutamide-resistant MR49F cells expresses low UGT2B17 mRNA but strong protein expression, suggesting that posttranslational mechanisms may enhance UGT2B17 protein stability in these cells. We then constructed PCa cell lines with gain-of-function UGT2B17 by lentivirus. Functional analyses indicate that UGT2B17 stimulates cancer cell proliferation, invasion, and xenograft progression to CRPC after prolonged androgen deprivation. To further decipher the molecular mechanisms by which UGT2B17 enhance PCa cell growth independent of androgen, we performed gene microarray using LNCaP(mock) and LNCaP(UGT2B17) cells cultured under the regular serum condition or the prolonged androgen deprivation condition. Microarray analyses reveal that UGT2B17 suppresses androgen-dependent AR transcriptional activity, while enhancing androgen (ligand)-independent AR transcriptional activity. The latter targets genes associated with cell mitosis. These UGT2B17 actions in reprogramming androgen signaling are mainly mediated by activating the c-Src kinase. We confirmed that, in CRPC tumors, UGT2B17 expression is positively associated with c-Src activation. Conclusion: These results indicate that UGT2B17 expedites CRPC progression by enhancing ligand-independent AR signaling that activates predominantly cell mitosis in cancer cells. Citation Format: Haolong Li, Ning Xie, Ruiqi Chen, Mélanie Verreault, Ladan Fazli, Martin E. Gleave, Olivier Barbier, Xuesen Dong. UGT2B17 promotes castration-resistant prostate cancer progression through enhancing ligand-independent AR signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1576. doi:10.1158/1538-7445.AM2017-1576
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".