Abstract A01: ADRB2 regulates phase II steroid metabolism and determines development of castration-resistant prostate cancer
Notice bibliographique
Résumé
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 We have unpublished data which shows that low expression of ADRB2 predicts a more rapid development of CRPC.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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».