Abstract 5463: YK5, a novel dual Hsc70 and Hsp70 inhibitor, is selective for tumor Hsp70 and has potent but selective activity in cancer cells
Notice bibliographique
Résumé
Abstract Background. The heat shock protein 70 (Hsp70) family members, heat-shock cognate 70 (Hsc70) and inducible Hsp70, are molecular chaperones abundantly expressed in human tumors. These proteins are necessary to maintain the dysregulated function and the anti-apoptotic potential of cancer cells. In this respect, the Hsp70 chaperones inhibit key effectors of the apoptotic machinery and are further involved in regulating kinases, hormone receptors and transcription factors that are directly involved in driving multistep malignancy and of mutated oncogenic proteins required for the transformed phenotype. Elevated Hsp70 expression, is characteristic of many tumor types and is associated with metastasis and poor prognosis, and is one of the major factors leading to resistance to anti-cancer therapy. The Hsp70 isoforms also contribute to tumorigenesis through their role as co-chaperones for the Heat shock protein 90 (Hsp90) molecular chaperone. The Hsp90 multi-chaperone complex, also called the Hsp90 super-chaperone machinery, has important roles in the development and progression of pathogenic cellular transformation through regulation of several malignancy driving and supporting client proteins. These biological functions propose Hsp70s as an important target whose inhibition may result in significant but selective apoptosis in a wide-range of cancer cells, and also in inhibition of signaling pathways involved in tumorigenesis and metastasis. Study design. In order to determine the role of Hsp70s modulation in cancer, we treated cancer cells of different origin with the novel dual Hsp70/Hsc70 inhibitor YK5, which is selective for tumor Hsp70s species. The effect of YK5 on the major cancer hallmarks, namely proliferation, cell cycle, apoptosis and invasiveness was evaluated. Results. Hsp70s modulation by YK5 has substantial and wide-ranging phenotypic consequence in cancer cells, directed through the Hsp90 machinery, and executed through disruption of functional Hsp90 machinery/onco-protein complexes. Modulation of Hsp70s also results in effects distinct from Hsp90, and we point out mechanistic differences between the two chaperones. Namely, unlike direct Hsp90 inhibitors, YK5 does not activate HSF-1 nor induces a protective feed-back heat shock response. When compared to direct Hsp90 inhibition, pharmacologic interference with Hsp70s results in increased, but yet selective cytotoxicity against cancer cells, mainly due to apoptosis. Further, we discover through YK5, that Hsp70s accelerate STAT1 dephosphorylation in breast cancer cells, identifying a novel mechanism that cancer cells use to inhibit the pro-apoptotic effects of this tumor suppressor. Conclusion. Our results propose Hsp70s inhibition by agents that act through an YK5-medited mechanism as a novel potent therapeutic approach in cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5463.
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) | 0,001 | 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 ».