Role of phospholipase A2s in gastrointestinal cancer

The widely conserved phospholipase A2 (PLAss) superfamily is made up of lipolytic enzymes consisting of 30 isoforms in nature with 22 isoforms expressed in humans. PLA2s have different tissue and cellular expression patterns and differ somewhat in their structure, which influences their secretion, enzymatic activity, and capacity to bind cellular receptors. PLA2s show specific enzymatic preferences for binding and hydrolysis of varying types of phospholipids. PLAss are divided into several subfamilies. In this chapter, the focus will be on two of these subfamilies, the secretory PLA2s (sPLA2s) and the cytoplasmic PLA2s (cPLA2s), where dysregulation of specific members of these subfamilies are implicated in all gastrointestinal (GI) cancers. In particular, there will be an emphasis on the role of the secretory phospholipase PLA2G2A and the cytoplasmic phospholipase PLA2G4A in GI cancers, as the role of these two genes/proteins have been the most extensively characterized thus far in GI cancers in human and animal models. Overall, it will be observed that the role of these PLA2s in GI cancers is very cell-, tissue-, species-, and cancer-dependent, and thus their general role in GI cancers is considered context-dependent. There is also a discussion of various mechanisms of action of these PLA2s including mediation of eicosanoid production, management of microbiota, inflammation, and catalysis-independent activity. Finally, there is a brief discussion of the various PLA2 inhibitor therapies that have been clinically tested or in current clinical trials.