Role and regulation of autophagy in cancer

Abstract

Autophagy is an evolutionarily conserved process whereby cytoplasm and cellular organelles are degraded in lysosomes for amino acid and energy recycling. Autophagy is a survival pathway activated in response to nutrient deprivation and other stressful stimuli, such as metabolic stress and exposure to anticancer drugs. However, autophagy may also result in cell death, if it proceeds to completion. Defective autophagy is implicated in tumorigenesis, as the essential autophagy regulator beclin 1 is monoallelically deleted in human breast, ovarian and prostate cancers, and beclin 1(+/-) mice are tumor-prone. How autophagy suppresses tumorigenesis is under intense investigation. Cell-autonomous mechanisms, involving protection of genome integrity and stability, and a non-cell-autonomous mechanism, involving suppression of necrosis and inflammation, have been discovered so far. The role of autophagy in treatment responsiveness is also complex. Autophagy inhibition concurrently with chemotherapy or radiotherapy has emerged as a novel approach in cancer treatment, as autophagy-competent tumor cells depend on autophagy for survival under drug- and radiation-induced stress. Alternatively, autophagy stimulation and preservation of cellular fitness by maintenance of protein and organelle quality control, suppression of DNA damage and genomic instability, and limitation of necrosis-associated inflammation may play a critical role in cancer prevention.

Fig. 1

Autophagy regulation. Growth factor signaling activates the PI3K/AKT/mTOR axis resulting in autophagy inhibition. Consequently, G-protein coupled receptor (GPCR) antagonists inhibiting growth factor receptors, lithium and carbamazepine negatively regulating class I PI3K, perifostine and AKT/PKB signaling inhibitor-2 (API-2) downregulating AKT activation, and rapamycin, RAD001 and CCI-779 inhibiting mTOR play pivotal roles in autophagy upregulation. In contrast, class III PI3K activates autophagy, and thus class III PI3K inhibitors such as 3-MA, wortmannin, LY294002 or PX-866 suppress autophagy. At least two pathways are responsible for autophagy activation in response to starvation and ER stress: one mediated by AMPK and CaMKK, and the other involving p53 and damage-regulated autophagy modulator (DRAM) activation. In this complex regulatory network, Ras exhibits dual function as both an autophagy inhibitor (via class I PI3K activation) and an autophagy activator (via the RAF1/MEK1/2/ERK1/2 pathway).