Abstract 6507: Inhibition of the translation initiation factor eIF4A1 enhances tumor cell radiosensitivity
Notice bibliographique
Résumé
Abstract The cellular radioresponse is regulated by constitutively expressed proteins and by new gene expression. We have previously shown that radiation induces changes in gene expression primarily via translational control. Regulation of gene translation largely occurs at the initiation stage, and many factors that regulate initiation impact the eukaryotic translation initiation factor 4F (eIF4F) complex. eIF4F is comprised of the cap-binding protein eIF4E, the RNA helicase eIF4A, and the scaffold protein eIF4G. Because eIF4A is considered to regulate the translation of mRNAs involved in cell survival and proliferation, we investigated it as a target for tumor cell radiosensitization. Knockdown of eIF4A1 in the U251 glioblastoma and the HeLa cervical carcinoma cell lines resulted in a decrease in translational efficiency as determined by polysome profiling and an increase in cellular radiosensitivity as determined by clonogenic survival analysis. There was also an increase in γH2AX foci remaining at 24h after irradiation, consistent with an inhibition of DNA double strand break repair. These results suggest that eIF4A serves as a determinant of cellular radiosensitivity. As an additional approach to inhibiting eIF4A, we utilized the rocaglate hydroxamate (-)-SDS-1-021, which prevents eIF4A inclusion into eIF4F. Treatment of U251, HeLa and PSN1 pancreatic carcinoma cells with 10 nM (-)-SDS-1-021 resulted in decreased translational efficiency, which was accompanied by a decrease in protein synthesis. Treatment of the tumor cell lines with (-)-SDS-1-021 immediately before radiation resulted in an increase in radiosensitivity as well as an increase in γH2AX foci remaining at 24h, similar to eIF4A1 knockdown. Importantly, whereas treatment of the normal human fibroblast cell line MRC9 with (-)-SDS-1-021 also inhibited translation and protein synthesis, there was no effect on radiosensitivity. To gain a better understanding of the mechanism of radiosensitization by (-)-SDS-1-021, RNAseq was performed using polysome-bound mRNAs isolated from U251 and MRC9 cells. Cells were treated with 10 nM (-)-SDS-1-021, immediately irradiated (2Gy), and then harvested six hours post-irradiation. In U251 cells treated with 2Gy alone, 192 genes were translationally upregulated. The upregulation of 160 of these genes was inhibited by (-)-SDS-1-021 in the combination treatment group. Similarly, in MRC9 cells, 322 genes were translationally upregulated in response to radiation, and the upregulation of 173 of these was inhibited in the combination treatment group. By Ingenuity Pathway Analysis, the radiation-induced, (-)-SDS-1-021-sensitive genes in U251 were significantly enriched for proteins involved in DNA replication, recombination, and repair, which is in contrast to the MRC9 (-)-SDS-1-021 genes. Altogether, these findings suggest that eIF4A1 is a viable target for tumor radiosensitization. Citation Format: Stacey L. Lehman, Theresa Wechsler, Kayla R. Schwartz, Amy Wahba, Lauren E. Brown, John A. Porco, Jerry Pelletier, Kevin Camphausen, Philip J. Tofilon. Inhibition of the translation initiation factor eIF4A1 enhances tumor cell radiosensitivity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6507.
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) | 0,001 | 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 ».