Calcium-independent phospholipase A_{2) (iPLA2) plays a pivotal role in phospholipid remodeling and many other biological processes, including inflammation and cancer development. iPLA{sub2} can be activated by caspase-3 via a proteolytic process in apoptotic cells. In this study, we identify novel signaling and functional loops of iPLA2 activation leading to migration of non-apoptotic human ovarian cancer cells. The extracellular matrix (ECM) protein, laminin-10/11, but not collagen I, induces integrin- and caspase-3-dependent cleavage and activation of over-expressed, and endogenous iPLA2. The truncated iPLA₂ (aa514-806) generates lysophosphatidic acid (LPA) and arachidonic acid (AA). AA is important for enhancing cell migration towards laminin-10/11. LPA activates Akt that in turn acts in a feedback loop to block the cleavage of poly-(ADP-ribose) polymerase (PARP) and DNA fragmentation factor (DFF), as well as prevent apoptosis. By using pharmacological inhibitors, blocking antibodies, and genetic approaches (such as point mutations, dominant negative forms of genes, and siRNAs against specific targets), we show that 1, but not 4, integrin is involved in iPLA₂ activation and cell migration to laminin-10/11. The role of caspase-3 in iPLA₂ activation and cell migration are supported by several lines of evidence: 1) point mutation of Asp513 (a cleavage site of caspase-3 in iPLA2) to Ala blocks laminin-10/11-induced cleavage and activation of over-expressed iPLA2, while mutation of Asp733 to Ala has no such effect; 2) treatment of inhibitors or a siRNA against caspase-3 results in decreased cell migration towards laminin-10/11; and 3) selective caspase-3 inhibitor blocks cleavage of endogenous iPLA₂ induced by laminin-10/11. Importantly, siRNA-mediated down regulation of endogenous iPLA₂ expression in ovarian carcinoma HEY cells results in decreased migration towards laminin, suggesting that our findings are pathophysiologically important.