Abstract A048 SR59230A-induced ferroptosis sensitization of Ewing sarcoma cells via Beta-3 adrenergic receptor modulation: A novel therapeutic target
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".