Abstract A01: ADRB2 regulates phase II steroid metabolism and determines development of castration-resistant prostate cancer
Bibliographic record
Abstract
Abstract The underlying mechanisms responsible for the development of castration-resistant prostate cancer (CRPC) are not fully understood. The β2-adrenergic receptor (ADRB2) is a key regulator of a wide range of metabolic processes in the body, and it has been implicated in androgen receptor signaling and development of CRPC. We have unpublished data which shows that low expression of ADRB2 predicts a more rapid development of CRPC. Based on this finding, we wanted to investigate whether the ADRB2 level/activity impacts cellular features to help explain how and why the receptor has prognostic value in prostate cancer. We stably transfected androgen-dependent LNCaP cells with shRNAs to mimic the clinical situation where patients have differential levels of ADRB2 in their prostate epithelial carcinomas. Gene expression profiling revealed changes in expression of several metabolic genes. Among the most regulated were two androgen-glucuronidating UDP-glucuronosyltransferase 2B (UGT2B) enzymes, UGT2B15 and UGT2B17. Both enzymes are critical in the phase-II metabolic pathway responsible for elimination of androgens by glucuronidation in the prostate, and they were highly down-regulated at the mRNA level in two LNCaP cell sublines expressing low levels of ADRB2 (shADRB2). By mixing androgen substrates with protein lysates from the cell and measuring glucuronide formation by LC-MS/MS, we found that glucuronide formation mirrored the UGT2B15/2B17 expression levels. To further complement these findings, we measured androgen levels in the cells by LC-MS, and found higher levels of bioactive testosterone. As this theoretically should invoke a change in androgen receptor activity of the cells, we measured androgen regulated luciferase activities as well as prostate-specific antigen (PSA/KLK3)-expression and secretion upon stimulation with the glucuronidable androgen dihydrotestosterone. The experiments revealed a noticeable increase in androgen responsiveness in cells with low levels of ADRB2 compared to cells with normal levels of ADRB2. Upon supplementation with the synthetic, non-glucuronidable androgen R1881, no induction in androgen responsiveness was observed in the shADRB2 cells compared to control cells. Dihydrotestosterone responsiveness was inhibited upon supplementation of diclofenac sodium, an inhibitor of UDP-glucuronosyltransferase actvity, and also upon rescue of ADRB2 expression level. Finally, using immunohistochemistry with an anti-UGT2B17 antibody, we found that patients showing strong cytoplasmic UGT2B17 immunostaining intensity progressed more rapidly to CRPC. Altering metabolic pathways, such as the steroid catabolic pathways, may be a powerful adaptive tool for cells to increase survival in an androgen-deprived micromilieu, and thus also a potential drug target. As LNCaP cells with low levels of ADRB2 display lowered glucuronidation activity, higher androgen responsiveness, and higher testosterone levels, we propose that this may be a novel metabolic mechanism by which ADRB2 affects the survival of androgen-dependent cells during androgen-deprivation therapy, and thereby development of CRPC. Citation Format: Peder Rustøen Braadland, Helene Hartvedt Grytli, Håkon Ramberg, Betina Katz, Lois Gauthier-Landry, Ralf Kellmann, Kurt Allen Krobert, Wanzhong Wang, Aud Svindland, Finn Olav Levy, Viktor Berge, Gunnar Mellgren, Olivier Barbier, Kristin Austlid Taskén. ADRB2 regulates phase II steroid metabolism and determines development of castration-resistant prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A01.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".