Deficiency in caspase-9 or caspase-3 induces compensatory caspase activation

Dysregulation of apoptosis contributes to the pathogenesis of many human di seases. As effecters of the apoptotic machinery, caspases are considered po tential therapeutic targets. Using an established in vivo model of Fas-medi ated apoptosis, we demonstrate here that elimination of certain caspases wa s compensated in vivo by the activation of other caspases. Hepatocyte apopt osis and mouse death induced by the Fas agonistic antibody Jo2 required pro apoptotic Bcl-2 family member Bid and used a Bid-mediated mitochondrial pat hway of caspase activation; deficiency in caspases essential for this pathw ay, caspase-9 or caspase-3, unexpectedly resulted in rapid activation of al ternate caspases after injection of Jo2, and therefore failed to protect mi ce against Jo2 toxicity. Moreover, both ultraviolet and gamma irradiation, two established inducers of the mitochondrial caspase-activation pathway, a lso elicited compensatory activation of caspases in cultured caspase-3(-/-) hepatocytes, indicating that the compensatory caspase activation was media ted through the mitochondria. Our findings provide direct experimental evid ence for compensatory pathways of caspase activation. This issue should the refore be considered in developing caspase inhibitors for therapeutic appli cations.