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2015 ; 10
(8
): e0135245
Nephropedia Template TP
Farhan MA
; Carmine-Simmen K
; Lewis JD
; Moore RB
; Murray AG
PLoS One
2015[]; 10
(8
): e0135245
PMID26295809
show ga
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.
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