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Review
. 2014 Oct;66(4):1033-79.
doi: 10.1124/pr.114.009217.

Phospholipase D signaling pathways and phosphatidic acid as therapeutic targets in cancer

Ronald C Bruntz  1 , Craig W Lindsley  1 , H Alex Brown  2
Affiliations
Review

Phospholipase D signaling pathways and phosphatidic acid as therapeutic targets in cancer

Ronald C Bruntz et al. Pharmacol Rev. 2014 Oct.

Abstract

Phospholipase D is a ubiquitous class of enzymes that generates phosphatidic acid as an intracellular signaling species. The phospholipase D superfamily plays a central role in a variety of functions in prokaryotes, viruses, yeast, fungi, plants, and eukaryotic species. In mammalian cells, the pathways modulating catalytic activity involve a variety of cellular signaling components, including G protein-coupled receptors, receptor tyrosine kinases, polyphosphatidylinositol lipids, Ras/Rho/ADP-ribosylation factor GTPases, and conventional isoforms of protein kinase C, among others. Recent findings have shown that phosphatidic acid generated by phospholipase D plays roles in numerous essential cellular functions, such as vesicular trafficking, exocytosis, autophagy, regulation of cellular metabolism, and tumorigenesis. Many of these cellular events are modulated by the actions of phosphatidic acid, and identification of two targets (mammalian target of rapamycin and Akt kinase) has especially highlighted a role for phospholipase D in the regulation of cellular metabolism. Phospholipase D is a regulator of intercellular signaling and metabolic pathways, particularly in cells that are under stress conditions. This review provides a comprehensive overview of the regulation of phospholipase D activity and its modulation of cellular signaling pathways and functions.

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Figures

Fig. 1.
Fig. 1.
Schematic of human PLD isoforms and splice variants. Human PLDs encode amino-terminal PX and PH domains followed by two catalytic HKD domains, characteristic of the PLD superfamily. PLD1a and PLD1b vary by 38 amino acids in a “loop” region between the two HKD domains. The PLD1c splice variant contains an early truncation mutation resulting in an inactive protein. Numbers indicate amino acid positions.
Fig. 2.
Fig. 2.
Cellular signaling modulating PLD activity from receptor tyrosine kinases and pathways downstream of PLD involved in oncogenic transformation.
Fig. 3.
Fig. 3.
Ligands reported to modulate PLD function either indirectly (e.g., 1 and 2), directly (e.g., 3–5) or alternative substrates to compete in a transphosphatidylation reaction with water (e.g., 6).
Fig. 4.
Fig. 4.
Structures and cellular PLD activity of halopemide (7) and the related analog FIPI (8), dual PLD1/PLD2 inhibitors with classic atypical antipsychotic promiscuous ancillary pharmacology.
Fig. 5.
Fig. 5.
Chemical optimization strategy for halopemide (7) employing a combination of diversity-oriented synthesis, and more focused iterative parallel synthesis. This effort led to the development of the 1700-fold PLD1-preferring inhibitor VU0359595 (9), the 75-fold PLD2-preferring VU0364739 (10), the >50-fold PLD2-selective MLPCN probe ML298 (11), and the potent dual PLD1/PLD2 inhibitor MLPCN probe ML299 (12). Importantly, ancillary pharmacology was improved significantly over compound 7 as well as PLD isoform selectivity.
Fig. 6.
Fig. 6.
PtdOH biosynthesis and metabolism. PtdOH is an intermediate in de novo triacylglycerol (TAG) biosynthetic pathway (i.e., the Kennedy pathway). It starts with glycerol-3-phosphate produced in the cell either via glycerol phosphorylation by glycerol kinase (GK) or from glucose via dihydroxyacetone phosphate and glycerol-3-phosphate dehydrogenase (G3P dehydrogenase). Glycerol-3-phosphate is sequentially acylated first at the sn-1 position by the enzyme glycerol-3-phosphate acyltransferase (GPAT; there are four known isoforms) using Acyl-CoA as a fatty acid donor to form LPA. This reaction is reversible and is catalyzed by PLA. LPA can be dephosphorylated to monoacylglycerol via lipid phosphate phosphatase (LPP), or as part of the Kennedy pathway, is further acylated at the sn-2 position again using Acyl-CoA as the fatty acid donor and carried out by 1-acylglycerol-3-phosphate acyltransferase, also known as lysophosphatidic acid acyltransferase (LPAAT) to generate PtdOH. This reaction is also reversible and catalyzed by LPA. PtdOH and DAG are “partners” in a synthetic route involving LPP also known as lipin or phosphatidic acid phosphatase, to generate DAG, which could be converted into PtdOH by diacylglycerol kinase (DGK; 10 known isoforms). Alternatively, DAG can be synthesized via acylation of monoacylglycerol by monoacylglycerol acyltransferase (MGAT) (also a reversible reaction). The final step is DAG esterification by diacylglycerol acyltransferase (DGAT; two known isoforms) to triacylglycerol. The reverse reaction is carried out by adipose triacylglycerol lipase (ATGL). PtdOH is also a product of PC hydrolysis catalyzed by PLD (two known isoforms). The remodeling pathway (Lands’ cycle) depends on the coordinated actions of PLA2 and lysophospholipid acyltransferases (LPLATs). Thus, PC can be hydrolyzed by PLA2 to form LPC, which can feed back into LPA via autotaxin (ATX)–carried out hydrolysis. Conversely, LPC can be reacylated back into PC with different fatty acyl substituents, supplied by Acyl-CoA and the action of lysophosphatidylcholine acyltransferase (LPCAT).
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