title: The inhibition of MAPK potentiates the anti-angiogenic efficacy of mTOR inhibitors.
abstract: 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.
authors: Department of Visceral Surgery, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Pavillon 3, Av. de Beaumont, 1011 Lausanne, Switzerland.
authors: Anne
authors: A
authors: Dormond-Meuwly
authors: Didier
authors: D
authors: Roulin
authors: Marc
authors: M
authors: Dufour
authors: Michael
authors: M
authors: Benoit
authors: Nicolas
authors: N
authors: Demartines
authors: Olivier
authors: O
authors: Dormond
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009025:Morpholines / Q000494:pharmacology; D046912:Multiprotein Complexes; D009369:Neoplasms / Q000201:enzymology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology; D009570:Nitriles / Q000494:pharmacology; D011506:Proteins / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014157:Transcription Factors / Q000037:antagonists & inhibitors
chemical_list: D020533:Angiogenesis Inhibitors; D002070:Butadienes; C493245:CRTC2 protein, human; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009025:Morpholines; D046912:Multiprotein Complexes; D009570:Nitriles; D011506:Proteins; D011743:Pyrimidines; D011804:Quinolines; D014157:Transcription Factors; C113580:U 0126; C541932:Ku 0063794; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C531198:dactolisib; D020123:Sirolimus