PMID- 26295809
OWN - NLM
STAT- MEDLINE
DCOM- 20160511
LR  - 20220318
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 10
IP  - 8
DP  - 2015
TI  - Endothelial Cell mTOR Complex-2 Regulates Sprouting Angiogenesis.
PG  - e0135245
LID - 10.1371/journal.pone.0135245 [doi]
LID - e0135245
AB  - 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.
FAU - Farhan, Maikel A
AU  - Farhan MA
AD  - Department of Medicine, University of Alberta, Edmonton, Canada.
FAU - Carmine-Simmen, Katia
AU  - Carmine-Simmen K
AD  - Department of Oncology, University of Alberta, Edmonton, Canada.
FAU - Lewis, John D
AU  - Lewis JD
AD  - Department of Oncology, University of Alberta, Edmonton, Canada.
FAU - Moore, Ronald B
AU  - Moore RB
AD  - Department of Surgery, University of Alberta, Edmonton, Canada.
FAU - Murray, Allan G
AU  - Murray AG
AD  - Department of Medicine, University of Alberta, Edmonton, Canada.
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150821
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Actins)
RN  - 0 (Indoles)
RN  - 0 (Morpholines)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Purines)
RN  - 0 (Pyrimidines)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (VEGFA protein, human)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 81HJG228AB (Ku 0063794)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.10.2 (Focal Adhesion Kinase 1)
RN  - EC 2.7.10.2 (PTK2 protein, human)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - H5669VNZ7V (PP242)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Actin Cytoskeleton/chemistry/genetics/metabolism
MH  - Actins/chemistry/genetics/metabolism
MH  - Carcinoma, Renal Cell/metabolism/pathology
MH  - Cell Adhesion
MH  - Cell Line, Tumor
MH  - Cell Movement
MH  - Coculture Techniques
MH  - Focal Adhesion Kinase 1/genetics/metabolism
MH  - Gene Expression Regulation
MH  - Human Umbilical Vein Endothelial Cells/cytology/drug effects/*metabolism
MH  - Humans
MH  - Indoles/pharmacology
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mechanistic Target of Rapamycin Complex 2
MH  - Morpholines/pharmacology
MH  - Multiprotein Complexes/antagonists & inhibitors/genetics/*metabolism
MH  - Neovascularization, Pathologic/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt/genetics/metabolism
MH  - Purines/pharmacology
MH  - Pyrimidines/pharmacology
MH  - RNA, Small Interfering/genetics/metabolism
MH  - Signal Transduction
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/genetics/*metabolism
MH  - Vascular Endothelial Growth Factor A/metabolism/pharmacology
PMC - PMC4546419
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2015/08/22 06:00
MHDA- 2016/05/12 06:00
PMCR- 2015/08/21
CRDT- 2015/08/22 06:00
PHST- 2015/04/23 00:00 [received]
PHST- 2015/07/20 00:00 [accepted]
PHST- 2015/08/22 06:00 [entrez]
PHST- 2015/08/22 06:00 [pubmed]
PHST- 2016/05/12 06:00 [medline]
PHST- 2015/08/21 00:00 [pmc-release]
AID - PONE-D-15-16881 [pii]
AID - 10.1371/journal.pone.0135245 [doi]
PST - epublish
SO  - PLoS One. 2015 Aug 21;10(8):e0135245. doi: 10.1371/journal.pone.0135245. 
      eCollection 2015.