Targeting phospholipase D with small-molecule inhibitors as a potential therapeutic approach for cancer metastasis

Abstract

Phospholipase D (PLD)1 and PLD2, the classic mammalian members of the PLD superfamily, have been linked over the past three decades to immune cell function and to cell biological processes required by cancer cells for metastasis. However, owing to the lack of effective small-molecule inhibitors, it has not been possible to validate these roles for the PLDs and to explore the possible utility of acute and chronic PLD inhibition in vivo. The first such inhibitors have recently been described and demonstrated to block neutrophil chemotaxis and invasion by breast cancer cells in culture, increasing the prospects for a new class of therapeutics for autoimmune disorders and several types of metastatic cancer.

Figure 1. Motifs and domains found within mammalian PLDs including PLD1, PLD2 and mitoPLD

HKD domains are essential for catalysis. The PX and PH domains are lipid-binding domains important for the regulation of PLD localization. The loop region, which is absent in PLD2, may play a negative regulatory role for PLD activity. The PIP2-binding domain is important for PLD localization and activity. The sites of interaction of PLD1 with its regulators are also highlighted. ARF: ADP-ribosylation factor; HKD: Histidine–lysine–aspartic acid; PH: Pleckstrin homology; PKC: Protein kinase C; PLD: Phospholipase D; PtdIns: Phosphoinositide; PX: Phox homology.