Autophagy modulation for cancer therapy

Abstract

Autophagy is a homeostatic and catabolic process that enables the sequestration and lysosomal degradation of cytoplasmic organelles and proteins that is important for the maintenance of genomic stability and cell survival. Beclin 1 (+/- ) gene knockout mice are tumor prone, indicating a tumor suppressor role for autophagy. Autophagy is also mechanism of stress tolerance that maintains cell viability and can lead to tumor dormancy, progression, and therapeutic resistance. Many anticancer drugs induce cytotoxic stress that can activate pro-survival autophagy. In some contexts, excessive or prolonged autophagy can lead to tumor cell death. Inhibition of cytoprotective autophagy by genetic or pharmacological means has been shown to enhance anticancer drug-induced cell death, suggesting a novel therapeutic strategy. Studies are ongoing to define optimal strategies to modulate autophagy for cancer prevention and therapy, and to exploit it as a target for anticancer drug discovery.

Figure 1

Autophagy pathway and relationship to mTOR signaling. Cellular stress (hypoxia, genotoxic, cytotoxic) activates autophagy as a stress response and cell survival mechanism. Inhibition of cytoprotective autophagy using 3-MA or CQ/HCQ can augment tumor cell death. Inhibition of mTOR induces autophagy, and in certain cellular contexts, excessive or sustained autophagy may promote cell death. mTOR inhibits autophagy by blocking the formation of ULK-Atg13-FIP200 trimeric complex.