The manuscript by Park et al. (Mol. Pharm. 2008; mol.107.042697 / PMID: 18182481) further defines the mechanism(s) by which OSU-03012 (OSU) kills transformed cells. It notes that in PKR-like endoplasmic reticulum kinase null cells (PERK-/-) the lethality of OSU is attenuated. OSU enhances the expression of ATG5 in a PERK-dependent fashion and promotes the ATG5-dependent formation of vesicles containing LC3, followed by a subsequent cleavage of cathepsin B and a cathepsin B-dependent formation of low pH intracellular vesicles; cathepsin B is activated and released into the cytosol, and genetic suppression of cathepsin B or AIF function significantly suppresses cell killing. In parallel, OSU causes PERK-dependent increases in HSP70 expression and decreases in HSP90 and Grp78/BiP expression. Inhibition of HSP70 expression enhances OSU toxicity and over-expression of HSP70 suppresses OSU-induced low pH vesicle formation and lethality. Thus, in this system PERK signaling promotes autophagy, which is causally linked to lysosomal dysfunction, cathepsin activation and cell death. However, in parallel, PERK signaling acts to suppress autophagy and lysosomal dysfunction by increasing the expression of HSP70. These findings may help explain why, in a cell type and stimulus-dependent fashion; autophagy has been noted to act either as a protective or as a toxic signal in cells.