The inhibition of MAPK potentiates the anti-angiogenic efficacy of mTOR inhibitors.

Détails

ID Serval
serval:BIB_881145C9CC33
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
The inhibition of MAPK potentiates the anti-angiogenic efficacy of mTOR inhibitors.
Périodique
Biochemical and Biophysical Research Communications
Auteur(s)
Dormond-Meuwly A., Roulin D., Dufour M., Benoit M., Demartines N., Dormond O.
ISSN
1090-2104 (Electronic)
ISSN-L
0006-291X
Statut éditorial
Publié
Date de publication
2011
Volume
407
Numéro
4
Pages
714-719
Langue
anglais
Résumé
The mammalian target of rapamycin (mTOR) which is part of two functionally distinct complexes, mTORC1 and mTORC2, plays an important role in vascular endothelial cells. Indeed, the inhibition of mTOR with an allosteric inhibitor such as rapamycin reduces the growth of endothelial cell in vitro and inhibits angiogenesis in vivo. Recent studies have shown that blocking mTOR results in the activation of other prosurvival signals such as Akt or MAPK which counteract the growth inhibitory properties of mTOR inhibitors. However, little is known about the interactions between mTOR and MAPK in endothelial cells and their relevance to angiogenesis. Here we found that blocking mTOR with ATP-competitive inhibitors of mTOR or with rapamycin induced the activation of the mitogen-activated protein kinase (MAPK) in endothelial cells. Downregulation of mTORC1 but not mTORC2 had similar effects showing that the inhibition of mTORC1 is responsible for the activation of MAPK. Treatment of endothelial cells with mTOR inhibitors in combination with MAPK inhibitors reduced endothelial cell survival, proliferation, migration and tube formation more significantly than either inhibition alone. Similarly, in a tumor xenograft model, the anti-angiogenic efficacy of mTOR inhibitors was enhanced by the pharmacological blockade of MAPK. Taken together these results show that blocking mTORC1 in endothelial cells activates MAPK and that a combined inhibition of MAPK and mTOR has additive anti-angiogenic effects. They also provide a rationale to target both mTOR and MAPK simultaneously in anti-angiogenic treatment.
Pubmed
Web of science
Open Access
Oui
Création de la notice
25/05/2011 9:15
Dernière modification de la notice
08/05/2019 21:31
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