Group VIB Ca²⁺-independent phospholipase A₂γ promotes cellular membrane hydrolysis and prostaglandin production in a manner distinct from other intracellular phospholipases A₂

Although group VIA Ca²⁺-independent phospholipase A ₂β (iPLA₂β) has been implicated in various cellular events, the functions of other iPLA₂ isozymes remain largely elusive. In this study, we examined the cellular functions of group VIB IPLA₂γ. Lentiviral transfection of IPLA₂γ into HEK293 cells resulted in marked increases in spontaneous, stimulus-coupled, and cell death-associated release of arachidonic acid (AA), which was converted to prostaglandin E₂ with preferred cyclooxygenase (COX)-1 coupling. Conversely, treatment of HEK293 cells with iPLA₂γ small interfering RNA significantly reduced AA release, indicating the participation of endogenous IPLA₂γ. iPLA₂γ protein appeared in multiple sizes according to cell types, and a 63-kDa form was localized mainly in peroxisomes. Electrospray ionization mass spectrometry of cellular phospholipids revealed that iPLA₂γ and other intracellular PLA₂ enzymes acted on different phospholipid subclasses. Transfection of iPLA₂γ into HCA-7 cells also led to increased AA release and prostaglandin E₂ synthesis via both COX-1 and COX-2, with a concomitant increase in cell growth. Immunohistochemistry of human colorectal cancer tissues showed elevated expression of iPLA₂γ in adenocarcinoma cells. These results collectively suggest distinct roles for iPLA₂β and iPLA₂γ in cellular homeostasis and signaling, a functional link between peroxisomal AA release and eicosanoid generation, and a potential contribution of iPLA₂γ to tumorigenesis.