Abstract P3-03-13: Chronic inhibition of signal transducer and activator of transcription 3/5 in treatment-resistant human breast cancer cell subtypes: Convergence on the reactive oxyten species/SUMOylation pathway and its effects on xCT expression and system xc- activity
Notice bibliographique
Résumé
Abstract Pharmacologically targeting activated signal transducer and activator of transcription 3 (STAT3) and/or STAT5 has been an active area of cancer research. The cystine/glutamate antiporter system xc- contributes to redox balance and export of intracellularly produced glutamate in response to up-regulated glutaminolysis in aggressive breast cancer cells. We have previously shown that blocking STAT3/5 using the novel small molecule inhibitor SH-4-54, designed to target the SH2 domains of both proteins, increases expression of xCT, which encodes the active component of system xc-, thereby increasing antiporter activity in human breast cancer cells. The current investigation demonstrates that chronic treatment with SH-4-54, followed by clonal selection of treatment-resistant MDA-MB-231 and T47D breast cancer cells, elicits distinct subtype-dependent effects. xCT mRNA and protein levels, glutamate release, and cystine uptake are decreased relative to untreated passage-matched controls in the triple-negative MDA-MB-231 SH-4-54-resistant clones, with the inverse occurring in estrogen-responsive T47D cells. This “ying-yang” effect is linked with a shifted balance between phosphorylated STAT3 and STAT5, intracellular levels of reactive oxygen species (ROS), STAT5 SUMOylation/de-SUMOylation, and the expression of STAT3/5 target genes (assessed by NextGeneration RNA sequencing). STAT5 emerged as a definitive negative transcriptional regulator of xCT, while STAT3 activation was coupled with increased system xc- activity. Specifically, inhibiting constitutive STAT3 phosphorylation in MDA-MB-231 cells induces ROS, thereby affecting the SUMO pathway by favoring de-SUMOylation and STAT5 phosphorylation. Activated STAT5 is then able to serve as a repressor by binding to its recognition sequence within the xCT promoter, reducing xCT expression and thereby destabilizing an important redox balancing mechanism by limiting cystine uptake through system xc-. In contrast, in ERα-positive cells that initially respond to STAT5-mediated signaling, STAT3 becomes activated and xCT expression is up-regulated in response to chronic SH-4-54 treatment, potentially leading to a more aggressive cancer subtype. Further destabilizing the cellular redox status may therefore be critical to produce clinically meaningful outcomes linked to chronic treatment with potent STAT3/5 inhibitors like SH-4-54. We assessed this notion by treating SH-4-54-resistant MDA-MB-231 clones with specific ROS-inducing reagents, including capsazepine, bleomycin, and paclitaxel, which produced different effects on cell viability. We propose that careful classification of a patient's breast cancer subtype is central to therapeutically targeting STAT3/5 as a means of treating breast cancer, particularly given that xCT is emerging as an important biomarker of aggressive cancers. Citation Format: Linher-Melville K, Nashed MG, Ungard R, Haftchenary S, Gunning PT, Singh G. Chronic inhibition of signal transducer and activator of transcription 3/5 in treatment-resistant human breast cancer cell subtypes: Convergence on the reactive oxyten species/SUMOylation pathway and its effects on xCT expression and system xc- activity [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-03-13.
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) | 0,003 | 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 ».