Abstract 314: Low-dose NAMPT inhibition by FK866 initiates autophagy to counteract cellular energy crisis, which is overridden by apoptosis at higher drug concentrations
Notice bibliographique
Résumé
Abstract Chronic lymphocytic leukemia (CLL) is characterized by accumulation of mature, but immune-incompetent monoclonal B-lymphocytes. Dependent on external stimuli, these CLL-cells can either be quiescent or active, with the latter being suggested to be critical for disease aggressiveness, drug-resistance and relapse. The active state of the malignant cells is associated with abnormal cellular metabolism. Nicotinamide adenine dinucleotide (NAD) is a critical factor in cellular metabolism by acting as coenzyme in ATP-synthesizing mitochondrial electron transport chain reactions. Nicotinamide phoysphorybosyltransferase NAMPT is the rate-limiting enzyme for nicotinamide-salvaging to NAD. NAMPT has been demonstrated to be over-expressed in several cancer entities. Also in CLL-cells increased NAMPT expression was found in tissue-associated CLL-cells by gene expression profiling. FK866 is a NAMPT-inhibitor and has been demonstrated to selectively reduce cancer cell viability mainly in solid tumors. FK866 has also been demonstrated to be effective in several hematological cell lines where it leads to ATP-reduction and delayed induction of cell death. While some studies proposed apoptosis-induction, others showed caspase-independent autophagic cell death. Most available data about the antitumor effect of FK866 is derived from studies in cell lines. Further, inconsistencies about sensitivity of different cell lines to FK866 in the literature strongly warrant studies in primary cells. In this study we address the impact of FK866-mediated NAMPT-inhibition on cellular energy content, cell viability and involvement of apoptotic and autophagic signaling in primary CLL-cells. FK866 potently reduced cellular NAD-content at low concentration of 10 nM as early as day one. This was followed by reduction in cellular ATP-content at day two and subsequent viability reduction at day three as assessed by flow cytometric measure of annexin V/PI staining. FK866 at 1 nM reduced cellular NAD-content slightly at day one with no significant further downregulation up to day four. At this drug concentration we neither saw significant ATP-downregulation, nor viability reduction up to day four. In contrast, at 1 nM FK866 we saw protection from spontaneous apoptosis by flow cytometry, stabilization of caspases 9 and 3, upregulation of antiapoptotic proteins XIAP and Mcl1 going along with increased phosphorylation of mTOR and AMPK. We conclude that downregulation of NAD by FK866 results in a cellular energy crisis, which CLL-cells counteract by initial induction of autophagy. At low FK866 concentrations this autophagic response is sufficient to compensate for energy loss and to prevent further downstream death signaling, while at higher concentration apoptosis overrides autophagy. Citation Format: Eric Bouchard, Iris Gehrke, Versha Banerji. Low-dose NAMPT inhibition by FK866 initiates autophagy to counteract cellular energy crisis, which is overridden by apoptosis at higher drug concentrations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 314. doi:10.1158/1538-7445.AM2014-314
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) | 0,005 | 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 ».