Abstract P5-07-05: Regulation of system Xc- by signal transducer and activator of transcription 3 and 5 in human breast cancer cells
Notice bibliographique
Résumé
Abstract In order to survive and proliferate, cancer cells adapt to high levels of oxidative stress by countering the accumulation of reactive oxygen species (ROS) with an increased production of intracellular antioxidant molecules such as glutathione. The cell surface transport system Xc- is a cystine/glutamate antiporter that exports glutamate while importing cystine, thereby mediating levels of cysteine required for glutathione synthesis and the maintenance of cellular redox balance. Transcription factors that regulate key antioxidant defense mechanisms, including system Xc-, may therefore be of therapeutic interest. Recently, signal transducer and activator of transcription (STAT) proteins have emerged as potential targets for the development of novel anti-cancer therapies. In particular, inhibitors of STAT3 and STAT5 may become clinically relevant as anti-cancer agents for breast and brain cancer, as well as leukemia. Interestingly, suppression of STAT3 has been linked with increases in ROS and the induction of apoptosis. Upon activation by phosphorylation, dimerization, and nuclear translocation, STAT proteins transcriptionally regulate diverse target genes by binding to promoter regions containing gamma-activated site (GAS) motifs. The human xCT (SLC7A11) gene encodes the functional subunit of system Xc-. We provide evidence that expression of xCT is regulated by STAT3, and potentially also STAT5, affecting antiporter function in both MCF-7 and MDA-MB-231 human breast cancer cells. Computational analysis of the xCT promoter region revealed the presence of a distal GAS site. Its truncation significantly increased luciferase activity in a reporter assay, with similar increases obtained after treating cells transfected with the full-length xCT promoter construct with various STAT3/5 pharmacologic inhibitors. Knock-down of STAT3 or STAT5A using specific siRNAs produced similar results, suggesting that these STAT proteins act in a transcriptionally repressive manner. We also demonstrated binding of STAT3 and STAT5A to the xCT promoter in MDA-MB-231 cells, which was disrupted by preincubating the cells with specific inhibitors. xCT mRNA and protein levels increased significantly following treatment with STAT3/5 inhibitors. Pharmacologically suppressing STAT3/5 activation also significantly increased glutamate release and total levels of intracellular glutathione. We hypothesize that blocking STAT3/5-mediated signaling induces an adaptive, compensatory mechanism that protects breast cancer cells from ROS by up-regulating Xc- antiporter expression and function. Our findings suggest that targeting system Xc- may synergize with STAT3/5 inhibitors, heightening their therapeutic anti-cancer effects, particularly in conjunction with traditional chemotherapy treatments. This work is supported by the Canadian Breast Cancer Foundation (CBCF). Citation Format: Katja Linher-Melville, Jennifer Fazzari, Patrick Gunning, Gurmit Singh. Regulation of system Xc- by signal transducer and activator of transcription 3 and 5 in human breast cancer cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-07-05.
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) | 0,004 | 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 ».