Novel Non-apoptotic Pathway of Caspase 3 Activation During Mild Oxidative Stress

Abstract

Caspases activation has been established as one of the hallmarks of apoptosis. Nevertheless, non-apoptotic roles of caspases have also been documented in recent years. The present study presented a novel non-apoptotic pathway leading to caspase 3 activation during mild oxidative stress. H2O2 (50?M) treatment activated caspase 3 independently of the initiator caspases and mitochondrial membrane permeabilization. The activation of caspase 3 is at sub-lethal level and activated caspase 3 was sustained in the nucleus. On the other hand, H2O2 treatment resulted in lysosomal membrane permeabilization (LMP) and subsequent cytosolic release of cathepsin B and L that activates caspase 3. Using pharmacological inhibition and molecular silencing approach, we identified iron, peroxynitrite, nitric oxide and p53 as upstream effectors of LMP and caspase 3 activation. Finally, we proposed a novel role of caspase 3 in lysosome biogenesis through regulation of expression and nuclear localization of the Transcription Factor for EB