Abstract A048 SR59230A-induced ferroptosis sensitization of Ewing sarcoma cells via Beta-3 adrenergic receptor modulation: A novel therapeutic target
Notice bibliographique
Résumé
Abstract Introduction: Ferroptosis acts as a tumor suppressor mechanism but also promotes cancer development due to its potential negative impact on anticancer immunity. Thus, a comprehensive understanding of the role of ferroptosis in cancer is crucial for the successful translation of ferroptosis therapy from in vitro to clinical applications. This form of cell death is particularly interesting to explore in ES as it could represent a mechanism to sensitize cells to chemotherapy treatment and potentially could avoid therapy resistance issue. In this scenario recent studies have shown that Beta-adrenergic receptors (β-ARs) sustain the pathogenesis of various malignant cancers. Furthermore, emerging evidences demonstrated the potential therapeutic role of a selective β3-AR antagonist (SR59230A) to sensitizing cancer cells. Notably, it could be involved in disrupting lipid metabolism in ES potentially leading to increased lipid peroxidation and triggering ferroptosis. Aim: Our study is aimed to identify new targets for innovative drug treatment that is desperately need to overcome tumor resistance of this inauspicious pediatric tumor. Methods: Viability was evaluated with MTS. The metabolic profile after SR59230a administration in A673 ES cell model was studied using the Seahorse XF Analyzer. Changes in gene expression was evaluated with RNA sequencing and Real-time PCR. Proteomic analysis was performed by western blot and immunofluorescence. Results: Our findings demonstrate that SR59230A (SR) sensitizes ES cells to treatment with the effect being more pronounced under starvation conditions, suggesting a potential drug-induced inhibition of fatty acid metabolism. Analysis of the ferroptosis pathway by RT-qPCR and Western blot, focusing on Glutathione Peroxidase 4 (GPX4), Nuclear Factor Erythroid 2-Related Factor 2 (NRF2), Transferrin Receptor (TFRC), and Lactate Dehydrogenase A (LDHA), revealed the potential involvement of this cell death mechanism. Notably, GPX4, a key enzyme in ferroptosis activation, was significantly upregulated, particularly after 24 hours of SR59230A treatment under starvation conditions. Additionally, XF Seahorse analysis indicated a reduction in mitochondrial ATP production (p = 0.01) following 24 hours of SR59230A treatment. RNA-seq analysis and Gsea pathway analysis consistently revealed a downregulation of the oxidative phosphorylation and an upregulation of ferroptosis pathway (p = 0.007), further supporting the involvement of SR in mitochondrial metabolism, particularly in fatty acid metabolism. These findings were further corroborated by the enhanced cytotoxic effect of SR in combination with deferoxamine, an iron chelator, as assessed by MTS assay. Conclusion: ES is a highly aggressive pediatric cancer, with a survival of ∼80% for patients with standard-risk and localized disease and ∼30% for those with metastatic disease. Our study unveils a novel therapeutic strategy by freezing the activity of β3AR with SR to sensitize resistant ES cells to chemotherapy through ferroptosis, a form of programmed cell death. Citation Format: Maria Ascone, Cristina Banella, Rachele Amato, Megan Lotti, Gianluca Mattei, Francesco Carrozzo, Amada Pasha, Annalisa Tondo, Maura Calvani. SR59230A-induced ferroptosis sensitization of Ewing sarcoma cells via Beta-3 adrenergic receptor modulation: A novel therapeutic target [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A048.
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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».