Abstract 2940: Identifying the minimal region of the ING1 tumor suppressor capable of efficiently killing cancer cells
Notice bibliographique
Résumé
Abstract ING1b is a type II tumor suppressor and a stoichiometric member of HDAC-containing protein complexes. ING1b overexpression promotes apoptosis, and decreased levels of ING1b are frequently observed in human tumors and cancer cell lines. Previously, we reported the identification of the regions of ING1b protein required for its pro-apoptotic function. Using deletion mutant analysis and transient expression in HEK293 cells we have determined that ING1b-derived peptides comprised of the NLS/NTS domain and the third alpha helix (A3H) of ING1b including the N-terminal portion of Lamin Interaction Domain (LID) are able to induce apoptosis at levels comparable to those of the full length ING1b, despite their lacking the PHD domain through which they affect the histone epigenetic code. Here, we report that adenoviral delivery of the A3H-NLS/NTS peptide led to a significant decrease in cell survival and induced apoptosis in a majority of tested cancer cell lines. The list of sensitive cancer cell lines was broad and included lines derived from both primary and metastatic tumor sources. As shown using an Annexin V binding assay, decreased survival of cells infected with adenovirus expressing A3H-NLS/NTS peptide was due to a large number of infected cells undergoing apoptosis. In fact, infecting triple negative tumorigenic MDA-MB-468 breast cancer line with 30 MOI of the Ad-A3H-NLS/NTS virus triggered rapid apoptosis in nearly 70% of infected cells. Importantly, these effects were time and dose dependent. Also, using a cell line carrying an inducible p53-expression system, we established that the ability of Ad-A3H-NLS/NTS to induce apoptosis is p53-independent. Next, we evaluated the cell death inducing properties of Ad-A3H-NLS/NTS using 10 breast cancer cell lines that were chosen based on their sensitivity to common HDAC inhibitors. While the overall sensitivity to Ad-A3H-NLS/NTS induced cell death varied among these lines, we observed no obvious correlation between the sensitivity to Ad-A3H-NLS/NTS and sensitivity/resistance to HDAC inhibitors. These findings suggest that Ad-A3H-NLS/NTS may have a broad application, including in those cancer cells lines that are normally resistant to conventional chemotherapy. Furthermore, combined application of Ad-A3H-NLS/NTS with either Trichostatin A (TSA) or Panobinostat (LBH-589) resulted in a strong additive, and possibly synergistic killing effect. Using the virus with either TSA or LBH-589 increased efficacy by nearly 3.5-fold as compared to the treatment with either TSA or LBH-589 along. Currently, the synergy between the Ad-A3H-NLS/NTS and common chemotherapeutics is being closely evaluated. Our long-term goal is to develop ING1b-based therapeutics that can be used as an adjuvant therapy in combination with existing cancer treatments. Citation Format: Oleksandr Boyko, Karl T. Riabowol. Identifying the minimal region of the ING1 tumor suppressor capable of efficiently killing cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2940. doi:10.1158/1538-7445.AM2015-2940
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 ».