Abstract A20: Investigating the role of SCO2 in the metabolic adaptation of cancer cells
Notice bibliographique
Résumé
Abstract SCO2 (synthesis of cytochrome c oxidase 2) is essential for the assembly and functioning of mitochondrial cytochrome c oxidase (COX) complex (IV). Mutations in the SCO2 gene have been reported to cause COX deficiency and result in fatal infantile cardioencephalomyopathy. Furthermore, the tumor suppressor protein p53 has been shown to mediate its effects on mitochondrial respiration via SCO2. SCO2-/- cells also exhibit increased intracellular oxygen and nicotinamide adenine dinucleotide (NADH) levels, leading to increased reactive oxygen species (ROS) and oxidative DNA damage. However, little is known regarding other metabolic adaptations triggered in response to SCO2 loss. To this end, metabolic profiling of wild-type (WT) and SCO2-/- colon cancer HCT116 cells was carried out using GC/MS. The steady-state levels of most of the glycolytic intermediates were higher in SCO2-/- as compared to WT cells with the exception of pyruvate. Moreover, an asymmetry was observed in the levels of the different tricarboxylic acid (TCA) cycle intermediates when contrasting WT and SCO2-/- cells. Citrate, malate, and alpha-ketoglutarate were elevated in WT relative to SCO2-/- HCT116 cells. In turn, succinate and 2-hydroxyglutarate were higher in SCO2-/- as compared to WT cells. Furthermore, the level of aspartate and asparagine was observed to be lower in the SCO2-/- HCT 116 compared to the WT HCT 116 cells, which is most likely to stem from the defects in oxidative phosphorylation caused by SCO2 loss. Stable isotope tracer analysis using 13C labeled glucose was done to monitor the flux of carbon atoms derived from glucose. As expected, SCO2-/- cells have minimal flux of carbon into the TCA cycle via acetyl CoA production due to the dysfunctional electron transport chain compared to the WT cells. However, SCO2-/- cells are still able to biosynthesize fumarate, malate and aspartate via pyruvate carboxylase. Hence, the SCO2-/- cells are still able to maintain TCA activity via pyruvate carboxylase, which may be necessary for their survival. Moreover, we observed alterations in mTOR signaling between SCO2-deficient and -proficient cells. Strikingly, rpS6 and 4E-BP1 were dramatically less phosphorylated in SCO2-/- cells as compared to WT, which illustrated a shutdown of mTORC1 activity upon SCO2 loss. In turn, AKT and likely mTORC2 activity were higher in SCO2-/- as compared to WT cells as illustrated by increased GSK3 and AKT phosphorylation. This suggests a rewiring of SCO2-/- cells whereby high AKT activity is not paralleled by increased mTOR activity, and we speculate that this is likely due to activation of AMPK. We hypothesize AMPK is activated to maintain energy balance in the cells where mitochondrial ATP production is reduced due to the loss of complex IV function. The changes may be important to the survival and proliferation of SCO2-/- cells and may explain the observed metabolic rewiring due to the loss of the gene. Citation Format: Alexandre V. Zhdanov, Oro Uchenunu, Nadezda A. Brazhe, Evelina Nikelshparg, Dmitry E. Andreev, Ruslan I. Dmitriev, Olga V. Sosnovtseva, Ivan Topisirovic, Dmitri B. Papkovsky. Investigating the role of SCO2 in the metabolic adaptation of cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr A20.
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 | 0,001 | 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 ».