Metformin mediated AMPK activation inhibits translation initiation in breast cancer cells
Notice bibliographique
Résumé
4470 The antidiabetic drug metformin lowers blood glucose by decreasing hepatic gluconeogenesis and stimulating glucose uptake in muscle. Some of the beneficial effects of metformin have been linked to the activation of the AMP activated protein kinase (AMPK) in muscle, adipose tissue, and liver, but effects of metformin on normal or transformed epithelial cells have not been well characterized. Upon activation, AMPK phosphorylates a number of effector proteins leading to the activation of ATP generating pathways, and the inhibition of ATP consuming pathways, such as protein synthesis. AMPK mediates its effects on protein synthesis through inhibition of the serine/threonine kinase, mTOR (mammalian target of rapamycin). mTOR is a major regulator of mRNA translation, and its effects on protein synthesis are mediated by two of its direct targets: the eIF4E binding proteins (4E-BPs) and the S6 protein kinase (S6K1), which are involved in regulating mRNA translation initiation. Inappropriate activation of mTOR can lead to increased cell growth, proliferation and neoplasia. Therefore, the inhibition of mTOR is being explored as a potential anti-cancer therapy. Recently we demonstrated ( Cancer Research 66:10269, 2006) that metformin inhibited the growth of breast cancer cells through the activation of AMPK. To extend this, we studied the effects of metformin on protein synthesis. Cells were treated with increasing doses of metformin for 24 hours and overall cellular translation was assessed by incorporation of 35 S methionine. In the breast cancer cell line MCF-7, metformin treatment led to a 30% decrease in protein synthesis. More specifically, the effect of metformin on cap-dependent translation was examined using a bicistronic reporter assay. Under these conditions, metformin caused a dose dependent decrease in cap-dependent translation, with a maximal inhibition of 40% at a dose of 20 mM. Polysome profile analysis also indicated an inhibition of translation initiation as metformin treatment of MCF-7 cells led to a decrease in heavy polysomes and a concomitant increase in the amount of 80S monosomes. The effects of metformin on translation were specifically mediated by AMPK, as treatment of cells with the AMPK inhibitor Compound C reversed the inhibition of protein synthesis. Furthermore, MDAMB-231 cells, which lack the AMPK regulator LKB1, were unaffected by metformin treatment. The effect of metformin on cellular translation was associated with mTOR inhibition and a decrease in the phosphorylation of ribosomal protein S6, and 4E-BP1. These results demonstrate that metformin-mediated AMPK activation leads to an inhibition of mTOR and a reduction in translation initiation, thus providing a mechanism for direct inhibition of cancer cell growth, separate from any growth inhibition that may relate to metformin-induced reduction of insulin levels in vivo .
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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) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| 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 ».