The Role of Phospholipase D Enzyme(s) in Modulating Cell Signaling: Implications for Cancer Drug Development

Phospholipases (PLC, PLD, and PLA) are essential in extracellular and intracellular signaling. This family of phosphopipid-hydrolizing enzymes can generate many bioactive lipid signaling molecules such as phosphatidic and lysophosphatidic acid, arachidonic acid, and diacylglycerol (DAG). The lipids produced from phospholipase enzyme activity regulate many cellular events considered hallmarks of cancerous behaviors in cells; including proliferation, migration, invasion, and angiogenesis. Mammalian phospholipase D enzymes have a complex intermediary role in many well characterized signal transduction pathways involving membrane-linked and cytosolic soluble signaling pathways. Regulation of this class of enzymes is complex: protein kinase C, ARF, and RHO proteins are identified as activators of PLD. The lipophilic product of PLD cleavage, phosphatidic acid (PA), acts as a second messenger in cells and has been shown to modulate many signaling molecules such as RAF, mTOR, S6K, and RAC. In the past decade, a more complete view of PLD enzymes, role within intracellular signaling has emerged. A thorough understanding of the cancer-associated signaling networks of the phospholipases and their products is beginning to emerge. Increased understanding of PLD’s role within cell growth and metabolism has facilitated its emergence as a potential target for cancer therapy. Novel, highly specific molecules are being identified and modified to potently inhibit this important enzyme in human intracellular signaling.