PLA(2) activity is required for nuclear shrinkage in caspase-independent cell death

Apoptosis is defined on the basis of morphological changes like nuclear fragmentation and chromatin condensation, which are dependent on caspases. Many forms of caspase-independent cell death have been reported, but the mechanisms are still poorly understood. We found that hypoxic cell death was independent of caspases and was associated with significant nuclear shrinkage. Neither Bcl-2 nor Apaf-1 deficiency prevented hypoxic nuclear shrinkage. To understand the molecular mechanism of the nuclear shrinkage, we developed an in vitro system using permeabilized cells, which allowed us to purify a novel member of the phospholipase A(2) (PLA(2)) family that induced nuclear shrinkage. Purified PLA(2) induced nuclear shrinkage in our permeabilized cell system. PLA(2) inhibitors prevented hypoxic nuclear shrinkage in cells and cell death. Hypoxia caused elevation of PLA(2) activity and translocation of intracellular PLA(2)s to the nucleus. Knockdown of the Ca(2+)-independent PLA(2) delayed nuclear shrinkage and cell death. These results indicate that Ca(2+)-independent PLA(2) is crucial for a caspase-independent cell death signaling pathway leading to nuclear shrinkage.