Cytosolic phospholipase A 2 α regulates G 1 progression through modulating FOXO1 activity

Group IVA phospholipase A 2 [cytosolic phospholipase A 2 α (cPLA 2 α)] 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 cPLA 2 α promotes cell proliferation. We identified 2 cpla 2 α genes in zebrafish, cpla 2 αa and cpla 2 αb , with conserved phospholipase activity. In zebrafish, loss of cpla 2 α expression or inhibition of cpla 2 α activity diminished G 1 progression through the cell cycle. This phenotype was also seen in both mouse embryonic fibroblasts and mesangial cells. G 1 progression was rescued by the addition of arachidonic acid or prostaglandin E 2 (PGE 2 ), indicating a phospholipase‐dependent mechanism. We further show that PGE 2 , 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 G 1 progression. Finally, using pharmacologic inhibitors, we show that cPLA 2 α, rapidly accelerated fibrosarcoma (RAF) /MEK/ERK, and PI3K/AKT signaling pathways cooperatively regulate G 1 progression in response to platelet‐derived growth factor stimulation. In summary, these data indicate that cPLA 2 α, through its phospholipase activity, is a critical effector of G 1 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.—Naini, S. M., Choukroun, G. J., Ryan, J. R., Hentschel, D. M., Shah, J. V., Bonventre, J. V., Cytosolic phospholipase A2α regulates G1 progression through modulating FOXO1 activity. FASEB J. 30, 1155–1170 (2016). www.fasebj.org