Exp Mol Med.  2014 Dec;46(12):e126. 10.1038/emm.2014.86.

Phospholipase D activates HIF-1-VEGF pathway via phosphatidic acid

• Han S
• Huh J
• Kim W
• Jeong S
• Min DS
• Jung Y

• KMID: 2155391
• DOI: http://doi.org/10.1038/emm.2014.86

Abstract

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.

MeSH Terms

Cell Line, Tumor
Epidermal Growth Factor/metabolism
Gene Expression Regulation, Neoplastic
Glioma/genetics/*metabolism
Humans
Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism
Phosphatidic Acids/*metabolism
Phospholipase D/genetics/*metabolism
*Signal Transduction
Transfection
Vascular Endothelial Growth Factor A/*metabolism
Hypoxia-Inducible Factor 1, alpha Subunit
Phosphatidic Acids
Vascular Endothelial Growth Factor A
Epidermal Growth Factor
Phospholipase D