The results presented here and previously demonstrate that DON-induced rRNA cleavage requires prior sequential activation of PKR/Hck, p38, p53, and caspases (Fig. 9) . It was remarkable that ricin, which possesses N-glycosidase enzymatic activity for 28S rRNA depurination, induced the identical rRNA cleavage profile to that of DON and two other low molecular weight translational inhibitors, SG and anisomycin. Possibly, in all four cases, toxin-mediated ribosome damage activated a canonical apoptosis-associated rRNA cleavage pathway. Future work should focus on understanding how DON mediates PKR activation, identifying critical executing caspases and RNases, ascertaining whether induction of rRNA cleavage by other ribotoxins or apoptosis-inducing agents is mediated by the same intracellular signaling pathways as well as validating these findings in animal models.