Abstract A17: NUAK1 acts as a growth suppressor in epithelial ovarian cancer
Notice bibliographique
Résumé
Abstract Epithelial ovarian cancer (EOC) cells form multicellular aggregates, or spheroids, and enter a dormant state during intraperitoneal metastasis. Dormant spheroids reduce anabolic metabolism and cell proliferation, which are linked to chemo-resistance. Liver kinase B1 (LKB1), encoded by the STK11 gene, is a critical regulator of stress metabolic signaling; LKB1 phosphorylates the downstream substrates AMP-activated protein kinase (AMPK) and AMPK-related kinases (ARKs) to mediate stress signaling. We have demonstrated that LKB1 expression and activity is required for EOC spheroid cell survival, yet knockdown of AMPKα1/α2 has no effect on viability. In addition, we have preliminary data demonstrating that phosphorylated AMPK is still maintained in EOC spheroids generated from CRISPR-mediated STK11-deleted cells, which completely lack LKB1 expression. Taken together, these results implicate the importance of other AMPK-independent effectors of LKB1 signaling in spheroid cell viability. Therefore, to identify critical downstream targets of LKB1-mediated signaling in EOC spheroids, we employed multiplex inhibitor beads/mass spectrometry (MIB/MS) using OVCAR8 STK11-knockout cells and OVCAR8 control cells grown in adherent and spheroid culture conditions. Using this proteomic approach, we identified NUAK1 as the sole ARK out of 12 different family members that is negatively affected by LKB1 loss. In fact, both phosphorylated and total NUAK1 protein expression are decreased in STK11-knockout cells and spheroids. NUAK1 can negatively control cell growth and proliferation by direct regulation of cell cycle checkpoint proteins in several cell systems; however, it has been relatively understudied in EOC. In analysis of the serous ovarian carcinoma data from TCGA, NUAK1 is infrequently altered (<2% of tumors) and it has the highest mean mRNA expression level as compared with the other 11 ARK genes. However, using immunoblot analysis, we show that NUAK1 protein is largely underexpressed in many established (n=15) and new ascites-derived EOC cell lines (n=22). In fact, further NUAK1 knockdown increased spheroid cell viability, size, and reattachment capability, whereas knockdown of its closely-related family member NUAK2 had no effect compared with the non-targeting siRNA control. Likewise, treatment with the pharmacologic NUAK1/2 inhibitor WZ4003 increased EOC cell growth and clonogenicity. Conversely, ectopic overexpression of NUAK1 reduced EOC cell growth and clonogenicity. Collectively, our data indicate that NUAK1 acts as a newly identified growth suppressor downstream of LKB1 metabolic stress signaling in EOC. We are currently investigating mechanisms regulating NUAK1 protein stability and activity in EOC cells, and whether activated LKB1-NUAK1 signaling promotes stress metabolic signaling during tumor dormancy in the context of EOC metastasis. Citation Format: Parima Saxena, Olga Collins, Yudith Ramos Valdes, Adrian Buensuceso, Kyle Francis, Kevin Brown, Karen Colwill, Anne-Claude Gingras, Robert Rottapel, Gabriel E. DiMattia, Trevor G. Shepherd. NUAK1 acts as a growth suppressor in epithelial ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A17.
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 ».