PloS one, 2015-08, Vol.10 (8), p.e0135245-e0135245
2015
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- Autor(en) / Beteiligte
- Titel
- Endothelial Cell mTOR Complex-2 Regulates Sprouting Angiogenesis
- Ist Teil von
- PloS one, 2015-08, Vol.10 (8), p.e0135245-e0135245
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2015
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Tumor neovascularization is targeted by inhibition of vascular endothelial growth factor (VEGF) or the receptor to prevent tumor growth, but drug resistance to angiogenesis inhibition limits clinical efficacy. Inhibition of the phosphoinositide 3 kinase pathway intermediate, mammalian target of rapamycin (mTOR), also inhibits tumor growth and may prevent escape from VEGF receptor inhibitors. mTOR is assembled into two separate multi-molecular complexes, mTORC1 and mTORC2. The direct effect of mTORC2 inhibition on the endothelium and tumor angiogenesis is poorly defined. We used pharmacological inhibitors and RNA interference to determine the function of mTORC2 versus Akt1 and mTORC1 in human endothelial cells (EC). Angiogenic sprouting, EC migration, cytoskeleton re-organization, and signaling events regulating matrix adhesion were studied. Sustained inactivation of mTORC1 activity up-regulated mTORC2-dependent Akt1 activation. In turn, ECs exposed to mTORC1-inhibition were resistant to apoptosis and hyper-responsive to renal cell carcinoma (RCC)-stimulated angiogenesis after relief of the inhibition. Conversely, mTORC1/2 dual inhibition or selective mTORC2 inactivation inhibited angiogenesis in response to RCC cells and VEGF. mTORC2-inactivation decreased EC migration more than Akt1- or mTORC1-inactivation. Mechanistically, mTORC2 inactivation robustly suppressed VEGF-stimulated EC actin polymerization, and inhibited focal adhesion formation and activation of focal adhesion kinase, independent of Akt1. Endothelial mTORC2 regulates angiogenesis, in part by regulation of EC focal adhesion kinase activity, matrix adhesion, and cytoskeletal remodeling, independent of Akt/mTORC1.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0135245Titel-ID: cdi_plos_journals_1720050700
- Format
- –
- Schlagworte
- Actin, Actin Cytoskeleton - chemistry, Actin Cytoskeleton - genetics, Actin Cytoskeleton - metabolism, Actins - chemistry, Actins - genetics, Actins - metabolism, Activation, Adhesion, AKT protein, AKT1 protein, Angiogenesis, Apoptosis, Brain cancer, Breast cancer, Cancer, Cancer therapies, Carcinoma, Renal Cell - metabolism, Carcinoma, Renal Cell - pathology, Cell Adhesion, Cell adhesion & migration, Cell Line, Tumor, Cell Movement, Coculture Techniques, Cytoskeleton, Deactivation, Drug resistance, Drug therapy, Endothelial cells, Endothelium, Focal adhesion kinase, Focal Adhesion Kinase 1 - genetics, Focal Adhesion Kinase 1 - metabolism, Gene Expression Regulation, Genetic aspects, Human Umbilical Vein Endothelial Cells - cytology, Human Umbilical Vein Endothelial Cells - drug effects, Human Umbilical Vein Endothelial Cells - metabolism, Humans, Inactivation, Indoles - pharmacology, Inhibition, Inhibitors, Kidney cancer, Kinases, Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, Molecular chains, Morpholines - pharmacology, Multiprotein Complexes - antagonists & inhibitors, Multiprotein Complexes - genetics, Multiprotein Complexes - metabolism, Neovascularization, Neovascularization, Pathologic - genetics, Neovascularization, Pathologic - metabolism, Pharmacology, Phosphorylation, Physiological aspects, Polymerization, Proteins, Proto-Oncogene Proteins c-akt - genetics, Proto-Oncogene Proteins c-akt - metabolism, Purines - pharmacology, Pyrimidines - pharmacology, Rapamycin, Renal cell carcinoma, Ribonucleic acid, RNA, RNA, Small Interfering - genetics, RNA, Small Interfering - metabolism, RNA-mediated interference, Signal Transduction, Sirolimus - pharmacology, TOR protein, TOR Serine-Threonine Kinases - antagonists & inhibitors, TOR Serine-Threonine Kinases - genetics, TOR Serine-Threonine Kinases - metabolism, Tumors, Vascular endothelial growth factor, Vascular Endothelial Growth Factor A - metabolism, Vascular Endothelial Growth Factor A - pharmacology, Vascularization