Abstract 5096: Alterations in cholesterol regulation contribute to the production of intratumoral androgens in castration-resistant prostate cancer
Notice bibliographique
Résumé
Abstract BACKGROUND: Prostate cancer (CaP) is the most commonly diagnosed cancer and third leading cause of cancer-related death in North American males. Recent evidence suggests that androgens mediate disease progression as recurrent CaP tumors contain androgens in levels high enough to activate the androgen receptor (AR). We have previously shown that in the absence of exogenous androgens, CaP cells develop the ability to synthesize their own androgens. We hypothesize that a) androgens induce the in vitro expression and activity of cholesterol synthesis and esterification pathways and b) cholesterol synthesis, influx and efflux are altered in vivo to provide precursors for de novo androgen synthesis contributing to castration-resistant prostate cancer progression. METHODS: We have analyzed cholesterol metabolism in vitro (LNCaP, PC-3 and C4-2 cells in the presence of androgens) and in vivo (LNCaP xenograft model). The LNCaP xenograft model was used to mimic clinical progression of the disease. Tumors were excised from the same mouse at three stages: Androgen-Dependent (AD, prior to castration), Nadir (N, 8-days post castration) and Castration-Resistance (CRPC, 35-days post castration) and stored for further analysis. Protein expressions of AR, PSA and proteins involved in cholesterol synthesis and metabolism, influx and efflux as well as actin were determined by immunoblotting. Total cholesterol concentrations were determined within each excised tumor using a fluorescent assay and LC-MS. Tumoral steroid levels were assessed by LC-MS. RESULTS: Microsomal PC-3 and LNCaP cell HMG CoA reductase (cholesterol biosynthesis) activity was increased upon androgen treatment. ACAT1 activity (cholesterol esterification) was induced by androgens in PC-3 cells and this induction was AR- dependent as well as associated with increased ACAT1 protein expression. Tumor LDLr, SR-BI, HMG CoA reductase, ACAT1 and 2 as well as ABCA1 were altered during disease progression to CRPC likely to increase influx and synthesis of cholesterol. Total cholesterol levels increased in N and CRPC compared to AD. HMG CoA reductase expression was upregulated in N compared to AD (300%) and was maintained at this level at CRPC. Tumoral cholesterol biosynthesis ex vivo was increased from N to CRPC. Testosterone and dihydrosterone increased at CRPC to physiologically relevant levels and this may account for the increase in AR activation as determined by PSA expression at CRPC. CONCLUSIONS: Cellular cholesterol processes are altered by androgens and during progression to CRPC. Cholesterol from increased biosynthesis or uptake is likely a precursor for tumoral de novo androgen synthesis. ACKNOWLEDGEMENTS: Funding for this project was provided by the Canadian Institutes of Health Research (CIHR) and an NCIC-Terry Fox Group grant. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5096.
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 machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| 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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
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 source (Gemma direct ou Codex distillé), 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 ».