The multiple roles of autophagy in cancer

Abstract

Autophagy is an evolutionarily conserved, catabolic process that involves the entrapment of cytoplasmic components within characteristic vesicles for their delivery to and degradation within lysosomes. Autophagy is regulated via a group of genes called AuTophaGy-related genes and is executed at basal levels in virtually all cells as a homeostatic mechanism for maintaining cellular integrity. The levels and cargos of autophagy can be modulated in response to a variety of intra- and extracellular cues to bring about specific and selective events. Autophagy is a multifaceted process and alterations in autophagic signalling pathways are frequently found in cancer and many other diseases. During tumour development and in cancer therapy, autophagy has paradoxically been reported to have roles in promoting both cell survival and cell death. In addition, autophagy has been reported to control other processes relevant to the aetiology of malignant disease, including oxidative stress, inflammation and both innate and acquired immunity. It is the aim of this review to describe the molecular basis and the signalling events that control autophagy in mammalian cells and to summarize the cellular functions that contribute to tumourigenesis when autophagy is perturbed.

Fig. 1.

Autophagic core machinery. The ULK kinase complex, the PI3K-III complex, mAtg9 and the two ubiquitination systems are indispensable for autophagy. Members of the core machinery are shown in coloured boxes. Modulators that are not part of the core machinery are shown in white boxes. For details, see text.

Fig. 2.

Autophagic vesicle generation and recycling. The first steps of autophagosome formation are initiation and nucleation. The earliest detectable autophagic structure is the double-membrane-bound phagophore/isolation membrane that evolves from the ER, mitochondria or the plasma membrane following activation of the ULK1 and Beclin 1 complexes (initiation/nucleation). Subsequently, the ATG16L complex, LC3-II and mAtg9 are recruited to the developing isolation membrane. The membraneous structure evolves (elongation) and encapsulates marcomolecules to become the closed hallmark structure of autophagy, the autophagosome. After fusion with a lysosome (maturation), the intra-vesicular constituents of the autophagosome get degraded and released into the cytosol, thereby creating a local rise in nutrient availability. This leads to reactivation of mTOR and regeneration of a mature lysosome from autolysosomes in a process called autophagic lysosome regeneration. Members of the core autophagic machinery that are involved in each step and can be found on the corresponding structure/vesicle are shown in coloured boxes. For details, see text.

Fig. 3.

Cellular and organismal functions that contribute to tumour development when autophagy is impaired. Shown is the impact of autophagy impairment on crucial cellular processes and how their alteration contributes to tumourigenesis. Importantly, oxidative stress is a recurring phenomenon in nearly all autophagy-impaired settings. For details, see text.

Fig. 4.

Consequences of impaired management of oxidative stress in autophagy-deficient cells. Impaired autophagy results in reduced clearance of p62 and damaged organelles, both of which can fuel ROS levels and thereby aggravate oxidative stress. Furthermore, p62 aggregation alters Nf-κB signalling to favour pro-survival signalling and therefore tumourigenic events. This vicious circle of increased ROS production and decreased clearance of ROS producers and p62 aggregates leads to genetic instability and an increased propensity to mutate DNA. As a result of overburdened ROS levels and DNA damage, the cells either die by necrosis and produce a pro-tumourigenic inflammatory response or a subset of cells acquire growth-promoting mutations. For details, see text.