1.Phospholipase D activates HIF-1-VEGF pathway via phosphatidic acid.
Songyi HAN ; Jeongsoon HUH ; Wooseong KIM ; Seongkeun JEONG ; Do Sik MIN ; Yunjin JUNG
Experimental & Molecular Medicine 2014;46(12):e126-
Growth factor-stimulated phospholipase D (PLD) catalyzes the hydrolysis of phosphatidylcholine (PC), generating phosphatidic acid (PA) which may act as a second messenger during cell proliferation and survival. Therefore, PLD is believed to play an important role in tumorigenesis. In this study, a potential mechanism for PLD-mediated tumorigenesis was explored. Ectopic expression of PLD1 or PLD2 in human glioma U87 cells increased the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) protein. PLD-induced HIF-1 activation led to the secretion of vascular endothelial growth factor (VEGF), a HIF-1 target gene involved in tumorigenesis. PLD induction of HIF-1alpha was significantly attenuated by 1-butanol which blocks PA production by PLD, and PA per se was able to elevate HIF-1alpha protein level. Inhibition of mTOR, a PA-responsive kinase, reduced the levels of HIF-1alpha and VEGF in PLD-overexpressed cells. Epidermal growth factor activated PLD and increased the levels of HIF-1alpha and VEGF in U87 cells. A specific PLD inhibitor abolished expression of HIF-1alpha and secretion of VEGF. PLD may utilize HIF-1-VEGF pathway for PLD-mediated tumor cell proliferation and survival.
Cell Line, Tumor
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Epidermal Growth Factor/metabolism
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Gene Expression Regulation, Neoplastic
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Glioma/genetics/*metabolism
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism
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Phosphatidic Acids/*metabolism
;
Phospholipase D/genetics/*metabolism
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*Signal Transduction
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Transfection
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Vascular Endothelial Growth Factor A/*metabolism