Abstract C284: IRE1 and PERK as targets of cellular adaptation and survival to hypoxia.
Notice bibliographique
Résumé
Abstract Hypoxia is an important and unique feature of the solid tumour microenvironment. Hypoxia promotes resistance to radiotherapy, aggressive disease phenotypes, and poor patient prognosis. Consequently, therapies directed against hypoxic cells are needed to improve patient outcome. Hypoxic stress leads to the activation of several adaptive pathways including the unfolded protein response (UPR). The UPR is activated in response to hypoxia-induced stress in the endoplasmic reticulum (ER) and consists of three distinct signaling pathways initiated by the ER-membrane resident proteins PERK, IRE1 and ATF6. Previous work using genetic models has implicated the PERK pathway, as well as downstream components of the IRE1 pathway (XBP1) as important mediators of hypoxia tolerance and tumor response to therapy. Here we employed short hairpin RNAs (shRNAs) and recently developed small-molecule inhibitors of IRE1 (4μ8c) and PERK (GSK-compound 39) to investigate the relative importance of these two pathways in promoting hypoxia tolerance and their potential as therapeutic targets. We tested the pathway activity of PERK and IRE1 by quantitative PCR and western blotting. Hypoxia tolerance was measured by in vitro clonogenic assays. First, knockdown experiments using two different shRNAs showed that IRE1 is essential for survival of HCT116 colorectal cancer cells during mild hypoxia while PERK was essential in both normoxia and hypoxia. Interestingly, the IRE1 knockdown cells had a significantly altered glycolytic metabolism, a known mechanism of hypoxia adaptation. Using our small-molecule IRE1 inhibitor, we show that 4μ8c is a potent and non-toxic inhibitor of IRE1 RNase activation in response to both hypoxia and other ER stress-inducing agents. This compound effectively inhibited IRE1 induced activation of the downstream target genes in both HCT116 colorectal cancer and KP4 pancreatic cancer cell lines under hypoxia. However, despite potent inhibition of IRE1 activation and the, 4μ8c had no effect on cell proliferation or clonogenic survival of HCT116 and KP4 cells during exposure to hypoxia or anoxia. Similarly, 4μ8c inhibition of IRE1 did not sensitize cells to other ER stress inducing agents. In contrast, genetic inactivation of PERK signaling or treatment with the highly selective and potent PERK inhibitor GSK-compound 39 substantially reduced tolerance to hypoxia, anoxia and other ER stress inducing agents. Our results demonstrate that although hypoxia potently activates both PERK and IRE1 arms of the UPR pathway, the PERK arm is uniquely important for promoting adaptation and survival during hypoxia-induced ER stress. Furthermore, our results suggest that newly developed and orally available PERK inhibitors such as GSK-compound 39 are selectively toxic to hypoxic cells, and thus warrant further development for use in combination therapies with radiation. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C284. Citation Format: Dan Cojocari, Ravi Vellanki, Brandon Sit, Marianne Koritzinsky, Bradly G. Wouters. IRE1 and PERK as targets of cellular adaptation and survival to hypoxia. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C284.
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 | 0,000 |
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 ».