Autophagic cell death unraveled: Pharmacological inhibition of apoptosis and autophagy enables necrosis

Abstract

Apoptosis is a well-characterized pathway to cell death, yet how it is related to other forms of cell death such as necrosis, and possibly also autophagic cell death has not been entirely clear. Difficulties arise because necrotic cell death is poorly characterized at the molecular level, and also because autophagy is primarily a survival pathway that has been associated with cell death induction in some circumstances. A common theme appears to be now emerging where autophagy promotes survival of apoptosis-defective cells, and inhibition of the autophagy survival function in this setting represents a means to divert cells into a necrotic cell fate. In cells denied the ability to commit suicide by apoptosis, and that are also unable to access the autophagy survival mechanism to sustain homeostasis, necrosis is the default activity. This was most recently illustrated with the discovery that the caspase and apoptosis inhibitor, zVAD, also inhibits a lysosomal protease, and thereby autophagy, and it is this dual inhibition that is responsible for induction of necrotic cell death.(1) This radically alters the interpretation of earlier findings reporting induction of autophagic cell death by zVAD,(2) instead, suggests that autophagy functions to promote cell survival.

Figure 1

Inhibition of cell death by apoptosis, and concomitant inhibition of survival by autophagy is a formula for induction of necrotic cell death. See text for explanation.