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

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-1α (HIF-1α) 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-1α was significantly attenuated by 1-butanol which blocks PA production by PLD, and PA per se was able to elevate HIF-1α protein level. Inhibition of mTOR, a PA-responsive kinase, reduced the levels of HIF-1α and VEGF in PLD-overexpressed cells. Epidermal growth factor activated PLD and increased the levels of HIF-1α and VEGF in U87 cells. A specific PLD inhibitor abolished expression of HIF-1α and secretion of VEGF. PLD may utilize HIF-1-VEGF pathway for PLD-mediated tumor cell proliferation and survival. Researchers in Korea have pieced together a molecular pathway that coordinates cellular proliferation and blood vessel formation in tumors. Many cancers exhibit hyperactive phospholipase D (PLD), an enzyme that contributes to cell growth. Excess activation of hypoxia-inducible factor-1α (HIFα), which promotes blood vessel growth in oxygen-poor conditions, is also a common feature of tumors. Yunjin Jung and colleagues at Pusan National University in Busan have now connected these two processes. Working with cultured brain tumor cells, the researchers show that PLD-mediated production of phosphatidic acid leads to increased HIFα activity. HIFα subsequently switches on numerous genes known to be stimulated by PLD activity. This sequence of events could be initiated by treatment with a signaling protein known to contribute to cancer onset, highlighting the likely importance of this PLD/HIFα pathway for tumor growth and survival.