The role of autophagy in tumour development and cancer therapy

Abstract

Autophagy is a catabolic membrane-trafficking process that leads to sequestration and degradation of intracellular material within lysosomes. It is executed at basal levels in every cell and promotes cellular homeostasis by regulating organelle and protein turnover. In response to various forms of cellular stress, however, the levels and cargoes of autophagy can be modulated. In nutrient-deprived states, for example, autophagy can be activated to degrade cargoes for cell-autonomous energy production to promote cell survival. In other contexts, in contrast, autophagy has been shown to contribute to cell death. Given these dual effects in regulating cell viability, it is no surprise that autophagy has implications in both the genesis and treatment of malignant disease. In this review, we provide a comprehensive appraisal of the way in which oncogenes and tumour suppressor genes regulate autophagy. In addition, we address the current evidence from human cancer and animal models that has aided our understanding of the role of autophagy in tumour progression. Finally, the potential for targeting autophagy therapeutically is discussed in light of the functions of autophagy at different stages of tumour progression and in normal tissues.

Figure 1

Mechanisms of autophagy. Following an initiating event, ATGs orchestrate the formation of autophagic vesicles from the phagophore/isolation membrane to the autophagosome and finally the autolysosome. The ULK–ATG13–FIP200 and the Beclin-1–hVps34–p150 complexes mediate early nucleation events, whereas the two ubiquitin-like conjugation systems (ATG5–ATG12 and LC3-II) direct vesicle elongation and autophagosome formation. Cellular material is finally sequestered within the autophagosome and thereby separated from the cytoplasm. Intracellular material is degraded in autolysosomes, which result from a fusion of lysosomes with autophagosomes. Importantly, autophagy is the complete process from initiation to degradation and not just the accumulation of autophagosomes. Abbreviations: ATG, autophagy-related protein; Beclin 1, coiled-coil myosin-like Bcl-2-interacting protein; FIP200, 200 kDa FAK family kinase-interacting protein; hVps34, human vacuolar protein sorting-associated protein 34; LC3, (microtubule-associated protein) light chain 3; mTOR, mammalian/mechanistic target of rapamycin; p150, regulatory subunit of hVps34; P, phosphorylation; ULK1/2, unc-51-like kinase 1/2.

Figure 2

Signalling networks of oncogenes and tumour suppressors that control autophagy. A multitude of pathways that are commonly deregulated in cancer control autophagy via its master switches mTOR and the complex of Beclin 1 and hVps34 (Beclin-1–hVps34). Hypoxia and limited nutrient supply are frequently encountered in tumours and lead to activation of autophagy via engagement of the same networks. Autophagy-inducing regulators are depicted in green, inhibiting regulators in red, and those that have a dual effect on autophagy in yellow. The asterisk indicates that the mechanism of Ras-induced upregulation of autophagy in senescence remains to be fully elucidated. Abbreviations: AKT, RAC-alpha serine/threonine-protein kinase; AMPK, AMP-activated protein kinase; ARHI, aplasia Ras homologue member I (also known as DIRAS3 for DIRAS family, GTP-binding RAS-like 3); BAD, Bcl-2-associated antagonist of cell death; Bcl-2, B-cell CLL/lymphoma 2 (apoptosis regulator); Bcl-X_L, B-cell lymphoma-extra large; Beclin 1, coiled-coil myosin-like Bcl-2-interacting protein; BIF1, endophilin B1; BNIP3(L), BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-(like); DAPK, death-associated protein kinase; DRAM1, damage-regulated autophagy modulator protein 1; ERK, extracellular-signal-regulated kinase; HIF1, hypoxia-inducible factor 1; MAP1B, microtubule-associated protein 1B; Mcl-1, induced myeloid leukaemia cell differentiation protein; mTORC1, mTOR complex 1; p53, cellular tumour antigen p53; p73, tumour protein p73; PDGFR, platelet-derived growth factors receptor; PDK1, 3-phosphoinositide-dependent protein kinase 1; PI3K-I, phosphoinositide 3-kinase class I; PTEN, phosphatase and tensin homologue; Ras, GTPase Ras; RTK, receptor tyrosine kinase; RHEB, Ras homologue enriched in brain; STK11, serine/threonine-protein kinase 11 (also known as LKB1); TSC1, hamartin, tuberous sclerosis 1 protein; TSC2, tuberin, tuberous sclerosis 2 protein; UVRAG, UV-radiation-resistance-associated gene.

Figure 3

Regulation of autophagy by Beclin 1 complexes. Beclin 1 exerts its function on autophagy only within a multimeric protein complex. It has diverse protein-binding domains that allow the formation of different complexes with opposing functions on autophagy. Certain stimuli, for example starvation, disrupt the binding of Bcl-2 proteins from the BH3 domain of Beclin 1. Beclin 1 can then bind and activate the phosphoinositide 3-kinase hVps34. Currently four regulators of the Beclin-1–hVps34 complex have been identified that determine its pro- or anti-autophagic activity. Autophagy-inducing regulators/complexes are depicted in green, inhibiting regulators/complexes in red, and those that have an undetermined role in yellow. Abbreviations: AMBRA1, activating molecule in Beclin-1-regulated autophagy protein 1; ATG, autophagy-related protein; BARKOR, Beclin-1-associated autophagy-related key regulator; Bcl-2, B-cell CLL/lymphoma 2; Bcl-X_L, B-cell lymphoma-extra large; Beclin 1, coiled-coil myosin-like Bcl-2-interacting protein; BH3, Bcl-2 homology domain 3; ECD, evolutionarily conserved domain; Mcl-1, induced myeloid leukaemia cell differentiation protein; Rubicon, RUN domain and cysteine-rich domain containing, Beclin-1-interacting protein; UVRAG, ultraviolet-radiation-resistance-associated gene.

Figure 4

Autophagy manages cellular stress to counteract tumour growth. In autophagy-competent cells, cellular stress leads either to cell death, growth arrest in the form of premature senescence, or survival. If the autophagic capacity falls below a threshold that is necessary to maintain cell integrity, for example through genetic alterations or pharmaceutical intervention, cells are unable to compensate metabolic stress. As a result, necrotic cell death occurs and causes attraction of tumour-promoting macrophages. In surviving cells, however, failure to clear p62 (sequestosome 1) and p62-associated aggregates results in further accumulation of ROS (reactive oxygen species), damaged proteins and organelles, altered cell signalling and DNA damage. Clinically, this phase might present as an initial tumour remission. However, the acquisition of growth-promoting mutations in a subset of cells might potentially lead to more aggressive tumour cells. Abbreviation: NF-κB, nuclear factor κB.