Identification of autophagic cell death and implications for therapy

Abstract

Autophagy is an evolutionarily conserved mechanism of bulk protein and organelle degradation that requires the ATG class of genes. Although autophagy has been frequently observed in dying cells in several species, a causative role for autophagy in cell death has not been demonstrated. We show that inhibition of caspase-8 in mouse L929 fibroblast cells causes cell death with the morphology of autophagy. Autophagic cell death in L929 cells is dependent on ATG genes and involves the receptor interacting protein (RIP) and the activation of the MAP kinase kinase 7(MKK7) - Jun N-terminal kinase (JNK) - cJUN pathway. We also show that autophagy occurs in many primary human tumors including cancer of the breast, lung and pancreas. Our findings validate autophagic cell death and might explain the role of autophagy in development, viral infections, neurodegenerative diseases and cancer.