15(S)-hydroxyeicosatetraenoic acid induces angiogenesis via activation of PI3K-Akt-mTOR-S6K1 signaling

Baolin Zhang, Huiqing Cao, Rao Gadiparthi

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)7283-7291
Number of pages9
JournalCancer Research
Volume65
Issue number16
DOIs
StatePublished - Aug 15 2005

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Phosphatidylinositol 3-Kinase
Hydroxyeicosatetraenoic Acids
Sirolimus
Endothelial Cells
Skin
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Phosphorylation
15-hydroxy-5,8,11,13-eicosatetraenoic acid
Arachidonate 5-Lipoxygenase
Eicosanoids

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

15(S)-hydroxyeicosatetraenoic acid induces angiogenesis via activation of PI3K-Akt-mTOR-S6K1 signaling. / Zhang, Baolin; Cao, Huiqing; Gadiparthi, Rao.

In: Cancer Research, Vol. 65, No. 16, 15.08.2005, p. 7283-7291.

Research output: Contribution to journalArticle

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