A277 DNA-PK SUSTAINS AUTOPHAGY AND PANCREATIC CANCER CELL GROWTH
Notice bibliographique
Résumé
Pancreatic cancer (PDAC) is currently the 4th leading cause of cancer related deaths in Canada. The life expectancy with metastatic PDAC is 3–6 months. Malignant pancreatic tumours are one of the most intrinsically resistant tumours that can withstand majority of the currently available treatment modalities. The tumours are showing resistance to Gemcitabine, the most commonly prescribed drug. Gemcitabine is known to induce DNA damage that, if not repaired, lead to cell death. Of note, it was observed that PDAC tissues display higher expression of DNA-PKcs, the catalytic subunit of DNA-PK involved in DNA repair, suggesting that DNA-PKcs and/or DNA-PK could provide a growth advantage to PDAC cells. Still, the role of DNA-PK in pancreatic pathophysiology remains elusive. Studies in the recent years have validated the high-basal levels of autophagy in PDAC cells and proven its importance in sustaining cell growth. It is noteworthy that agents inducing DNA damage have been correlated with autophagy modulation suggesting a potential link between autophagy-DNA damage and/or DNA repair mechanisms. However, the underlined mechanisms have yet to be identified. The overall objective was to interrogate a potential role for DNA-PK, increased in PDAC tissues, in regulating autophagy and growth of PDAC cells. The PDAC cell line MiaPaCa-2 was used. The specific inhibitor NU7441 was used to block DNA-PK activity. Cell counting and clonogenic assays were performed to assess cell growth. Autophagic flux was measured by co-treatment with the autophagy inhibitor Bafilomycin A1. 1) We observed a dose- and time-dependent decrease in cell number in DNA-PK inhibited cells as compared to control cells. 2) This coincides with the reduced colony forming ability of PDAC cells when treated with NU7441. 3) The impact on cell growth correlated with induction of cell apoptosis as measured by PARP and caspase-7 cleavage. 4) Given the reported role of autophagy in sustaining PDAC cell growth, we assessed the impact of DNA-PK inhibition on autophagy. Immunoblotting and immunofluorescence studies revealed that NU7441 treatment triggers increased expression of the autophagy receptor p62/SQSTM1 as well as lipidation of LC3B indicative of autophagy modulation. 5) Autophagy flux measurement supported blockade of autophagy upon DNA-PK inhibition. Taken together, our results demonstrate that interference with DNA-PK activity is an attractive avenue to abrogate PDAC cell growth. Our observations support a novel role for DNA-PK in regulating autophagy. Given that PDAC tissues were shown to display high expression levels of DNA-PKcs, it is tempting to speculate that DNA-PK could be involved in maintaining high basal levels of autophagy as observed in PDAC cells. NSERC, CRS
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) | 0,002 | 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 ».