Cytosolic phospholipase A2α regulates G1 progression through modulating FOXO1 activity.

Group IVA phospholipase A² [cytosolic phospholipase A²α (cPLA²α)] is a key mediator of inflammation and tumorigenesis. In this study, by using a combination of chemical inhibition and genetic approaches in zebrafish and murine cells, we identify a mechanism by which cPLA²α promotes cell proliferation. We identified 2 cplA²α genes in zebrafish, cplA²αa and cplA²αb, with conserved phospholipase activity. In zebrafish, loss of cplA²α expression or inhibition of cplA²α activity diminished G₁ progression through the cell cycle. This phenotype was also seen in both mouse embryonic fibroblasts and mesangial cells. G₁ progression was rescued by the addition of arachidonic acid or prostaglandin E2 (PGE2), indicating a phospholipase-dependent mechanism. We further show that PGE2, through PI3K/AKT activation, promoted Forkhead box protein O1 (FOXO1) phosphorylation and FOXO1 nuclear export. This led to up-regulation of cyclin D1 and down-regulation of p27^Kip1, thus promoting G₁ progression. Finally, using pharmacologic inhibitors, we show that cPLA²α, rapidly accelerated fibrosarcoma (RAF)/MEK/ERK, and PI3K/AKT signaling pathways cooperatively regulate G₁ progression in response to platelet-derived growth factor stimulation. In summary, these data indicate that cPLA²α, through its phospholipase activity, is a critical effector of G₁ phase progression through the cell cycle and suggest that pharmacological targeting of this enzyme may have important therapeutic benefits in disease mechanisms that involve excessive cell proliferation, in particular, cancer and proliferative glomerulopathies. [ABSTRACT FROM AUTHOR]