Targeting Metabolism and Autophagy in the Context of Haematologic Malignancies

Figure 2

Signaling pathways regulating autophagy and their inhibitors. Autophagy is a catabolic process that results in the autophagosomic-lysosomal degradation of bulk cytoplasmic contents. The kinase mTOR is a critical regulator of autophagy induction, with activated mTOR (PI3K/Akt) suppressing autophagy. AMPK-signaling negatively regulates mTOR signaling therefore promoting autophagy. ROS stress is an important inducer and regulator of autophagy generated by reduced oxidative phosphorylation and increased glycolysis. Nuclear 53 induces autophagy through transcriptional regulation of multiple genes whereas cytoplasmic p53 inhibits autophagy by blocking the mTOR pathway. Autophagy inhibitors chloroquine (HCQ/CQ) and metformin are under clinical investigation. Many chemotherapy/radiation therapies induce autophagy through ROS, inhibition of the mTOR pathway or nuclear p53 whereas PI3K/mTor inhibitors or rapamycin analogues specifically block the mTOR signaling pathway leading to autophagy.