Abstract 5561: 20(S)-Protopanaxadiol-aglycone downregulates full-length and ligand-independent splice variants of androgen receptor
Notice bibliographique
Résumé
Abstract Prostate carcinogenesis is characterized by a long latency of 20 to 40 years. Chemoprevention to manage the disease at an early stage to prevent it from becoming clinical relevant is increasingly being recognized as an important aspect of prostate cancer control. Androgen signaling plays a vital role in the development and progression of prostate cancer. Finasteride and dutasteride, which inhibit the formation of dihydrotestosterone, are the only chemopreventive agents that have been shown definitively to decrease prostate cancer incidence. However, their effectiveness appears to be limited to Gleason 6 cancers. In addition, cancer cells expressing high level of constitutively-active, ligand-independent splice variants of androgen receptor may not be responsive to treatment with finasteride or dutasteride. Therefore, there is an urgent need to develop new chemopreventive agents that could block androgen signaling through both the full-length and splice variants of androgen receptor. Ginsenosides are the main ingredients responsible for the pharmaceutical functions of ginseng, a commonly used medicinal herb among cancer patients. Several ginsenosides have been implicated to inhibit prostate cancer cell growth. However, the underlying mechanism is largely unknown. Here we provide the first evidence that, in prostate cancer cells, ginsenoside 20(S)-protopanaxadiol-aglycone (PPD) effectively downregulates the expression and activity of androgen receptor, including both the full-length and the constitutively-active, ligand-independent splice variants. The effect of PPD on androgen receptor is manifested by an immediate drop in protein, followed by a reduction in mRNA. The initial decrease in androgen receptor protein could be attributed to PPD induction of proteasome-mediated degradation, possibly as a result of disrupted androgen receptor N-C interaction. Depressing the inhibitory effect of PPD on androgen receptor by knocking down androgen receptor before PPD treatment weakens significantly the growth-suppressive activity of PPD, indicating the important contribution of androgen receptor downregulation to PPD action in prostate cancer cells. This report is also the first to establish the in vivo preclinical efficacy of PPD against the growth of androgen receptor-expressing prostate cancer cells, which constitute the majority of clinical prostate carcinomas. In addition to tumor growth inhibition, PPD supplementation also leads to in vivo downregulation of androgen receptor and its target gene, prostate-specific antigen. Considering the critical role of androgen receptor signaling in prostate cancer development and progression and the role of the ligand-independent androgen receptor splice variants in disease recurrence, our findings provide strong justification for further development of PPD for prostate cancer prevention and treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5561. doi:10.1158/1538-7445.AM2011-5561
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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 | 0,001 | 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 ».