PMID- 16103079
OWN - NLM
STAT- MEDLINE
DCOM- 20051027
LR  - 20211203
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 65
IP  - 16
DP  - 2005 Aug 15
TI  - 15(S)-hydroxyeicosatetraenoic acid induces angiogenesis via activation of 
      PI3K-Akt-mTOR-S6K1 signaling.
PG  - 7283-91
AB  - To determine whether the lipoxygenase metabolites of arachidonic acid, 5(S)-, 
      12(S)-, and 15(S)-hydroxyeicosatetraenoic acids [5(S)-HETE, 12(S)-HETE, and 
      15(S)-HETE, respectively] are angiogenic, we have studied their effects on human 
      dermal microvascular endothelial cell (HDMVEC) tube formation and migration. All 
      three HETEs stimulated HDMVEC tube formation and migration. Because 15(S)-HETE 
      was found to be more potent than 5(S)-HETE and 12(S)-HETE in HDMVEC tube 
      formation, we next focused on elucidation of the signaling mechanisms underlying 
      its angiogenic activity. 15(S)-HETE stimulated Akt and S6K1 phosphorylation in 
      HDMVEC in a time-dependent manner. Wortmannin and LY294002, two specific 
      inhibitors of phosphatidylinositol 3-kinase (PI3K), blocked both Akt and S6K1 
      phosphorylation, whereas rapamycin, a specific inhibitor of Akt downstream 
      effector, mammalian target of rapamycin (mTOR), suppressed only S6K1 
      phosphorylation induced by 15(S)-HETE suggesting that this eicosanoid activates 
      the PI3K-Akt-mTOR-S6K1 signaling in HDMVEC. Wortmannin, LY294002, and rapamycin 
      also inhibited 15(S)-HETE-induced HDMVEC tube formation and migration. In 
      addition, all three HETEs stimulated angiogenesis as measured by in vivo Matrigel 
      plug assay with 15(S)-HETE being more potent. Pharmacologic inhibition of 
      PI3K-Akt-mTOR-S6K1 signaling completely suppressed 15(S)-HETE-induced in vivo 
      angiogenesis. Consistent with these observations, adenoviral-mediated expression 
      of dominant-negative Akt also blocked 15(S)-HETE-induced HDMVEC tube formation 
      and migration and in vivo angiogenesis. Together, these results show for the 
      first time that 15(S)-HETE stimulates angiogenesis via activation of 
      PI3K-Akt-mTOR-S6K1 signaling.
FAU - Zhang, Baolin
AU  - Zhang B
AD  - Department of Physiology, University of Tennessee Health Science Center, Memphis, 
      Tennessee 38163, USA.
FAU - Cao, Huiqing
AU  - Cao H
FAU - Rao, Gadiparthi N
AU  - Rao GN
LA  - eng
GR  - HL74860/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Drug Combinations)
RN  - 0 (Hydroxyeicosatetraenoic Acids)
RN  - 0 (Laminin)
RN  - 0 (Proteoglycans)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 119978-18-6 (matrigel)
RN  - 73945-47-8 (15-hydroxy-5,8,11,13-eicosatetraenoic acid)
RN  - 9007-34-5 (Collagen)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (RPS6KA1 protein, human)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 90-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Cell Movement/drug effects/physiology
MH  - Collagen
MH  - Drug Combinations
MH  - Endothelial Cells/cytology/drug effects
MH  - Enzyme Activation
MH  - Humans
MH  - Hydroxyeicosatetraenoic Acids/antagonists & inhibitors/metabolism/*pharmacology
MH  - Laminin
MH  - Neovascularization, Physiologic/*drug effects
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphorylation/drug effects
MH  - Protein Kinases/*metabolism
MH  - Protein Serine-Threonine Kinases/biosynthesis/genetics/*metabolism
MH  - Proteoglycans
MH  - Proto-Oncogene Proteins/biosynthesis/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - Ribosomal Protein S6 Kinases, 90-kDa/*metabolism
MH  - Signal Transduction
MH  - Skin/*blood supply
MH  - TOR Serine-Threonine Kinases
EDAT- 2005/08/17 09:00
MHDA- 2005/10/28 09:00
CRDT- 2005/08/17 09:00
PHST- 2005/08/17 09:00 [pubmed]
PHST- 2005/10/28 09:00 [medline]
PHST- 2005/08/17 09:00 [entrez]
AID - 65/16/7283 [pii]
AID - 10.1158/0008-5472.CAN-05-0633 [doi]
PST - ppublish
SO  - Cancer Res. 2005 Aug 15;65(16):7283-91. doi: 10.1158/0008-5472.CAN-05-0633.