Zombie cells

Looks can be deceiving—even a cell that appears healthy may be doomed to die. Ekert et al. (page 835) report that cells lacking two important caspases can survive in the short term without a growth factor, but will succumb eventually. Thus, the normal job of these caspases may be to accelerate the dying process rather than control the commitment of cells to death.

The situation varies between organisms. In worms, deletion of CED-4 and CED-3 (the homologues of mammalian Apaf-1 and caspase-9) completely prevents programmed cell death. Some mice without Apaf-1 and caspase-9 die from neuronal overgrowth but others fare just fine. One possibility is that another caspase such as caspase-2 takes over when caspase-9 is absent or can't be activated by Apaf-1.

Ekert and colleagues used growth factor–dependent cell lines to study apoptosis when Apaf-1, caspase-9, or caspase-9 and -2 were missing. When deprived of the factor IL-3, none of the cells shrank, had blebbed membranes, or exhibited any other obvious apoptotic phenotypes. But closer examination revealed that, though normal to the naked eye, the cells had released cytochrome c from their mitochondria—a classic sign of apoptosis. To add insult to injury, the cells were essentially zombies. Even when IL-3 was restored to the medium they could not make clones. Marsden et al. (page 775) similarly find that lymphocytes and fibroblasts lacking caspase-2 and -9 remained sensitive to many apoptotic stimuli.

The cause of cell death in the caspase-deleted cells remains unclear. Mitochondrial ATP generation may be fatally compromised by the leakage of cytochrome c, another mitochondrial factor may leak out, or another caspase may initiate an irreversible event. Whatever the explanation, the current results suggest that the loss of certain caspases in cancer cells does not necessarily explain the increased survival of these cancer cells. ▪