Changes in cIAP 2, survivin and Bim EL expression characterize the switch from autophagy to apoptosis in prolonged starvation

Background Autophagy is a catabolic process involving the engulfment of cytoplasmic content within autophagosomes followed by their delivery to lysosomes. This process is a survival mechanism, enabling cells to cope with nutrient deprivation by degradation and recycling of macromolecules. Yet during continued stress such as prolonged starvation, a switch from autophagy to apoptosis is often detected. Objective In this work, we characterized the temporal dynamics of the transition from autophagy towards apoptosis with the aim of elucidating the molecular mechanism regulating the switch from survival autophagy to apoptotic cell death. Results and Conclusions We defined an inverse relationship between apoptosis and autophagy spanning a period of 72 h, manifested by the sequential reduction in LC 3 lipidation and the activation of caspase‐3. The transition to apoptosis correlated with a selective decline in the mRNA and protein levels of two anti‐apoptotic IAP family proteins, survivin and cIAP 2 and a selective increase in the BH 3‐only protein, Bim EL . This ‘molecular signature’ was common to several cell lines undergoing the switch from autophagy to apoptosis during prolonged starvation. Mechanistically, the increased Bim EL protein levels resulted from its reduced binding to its specific E3 ligase, βTr CP , leading to protein stabilization. Consistent with this, Bim EL showed decreased phosphorylation at critical sites previously reported to be essential for binding to the E3 ligase. The decrease in the anti‐apoptotic IAP s and the increase in the pro‐apoptotic Bim EL may thus constitute a molecular switch from autophagy to apoptosis during prolonged starvation.