Fig. 1

Autophagy A The basic autophagy machinery. Autophagy induction is controlled by AMPK and mTOR signaling pathways. Under nutrient/energy deficiency conditions, AMPK indirectly inhibits mTOR and directly activates ULK1 protein by the phosphorylation of activation sites at Ser-555 and Ser-637. Furthermore, ULK1 is a direct target of mTOR, whose inactivation prevents the inhibitory phosphorylation on Serine 638 and 758 of ULK1, promoting its further activation. Once activated, the ULK1 kinase complex translocates to the endoplasmic reticulum, followed by the autophagic PI3K complex I. PI3K complex phosphorylates the lipid phosphatidylinositol to generate a pool of PI3P which drives omegasome formation, recruiting other autophagy effectors and producing the active form of LC3B, commonly called LC3-II. In turn, LC3-II enables the docking of specific cargos and adaptor proteins at the phagophore membrane, such as p62, able to recognize cargos destined to be degraded by autophagy. The continuous assembly of the aforementioned complexes and the delivery of distal membrane compartments allow the phagophore to expand, enclosing a portion of the cytosol, and to form the mature autophagosome. Once formed, the autophagosome fuses with a lysosome, triggering the formation of an autolysosome. After degradation of its content by the action of lysosomal hydrolases, the recycled products are released into the cytosol to be reused by the cell. B Autophagy in cancer: two sides of the same coin. Autophagy has a complex and dual role in the pathogenesis of cancer, potentially acting either as a suppressor or a promoter of tumor development. Autophagy protects from malignant transformation by safeguarding genomic stability, removing oncogenic proteins, reducing reactive oxygen species, promoting autophagic cell death and inducing the clearance of intracellular pathogens. Likewise, autophagy favours tumor initiation and progression by providing an alternative energy source in the absence of oxygen and nutrients, promoting the resistance to anoikis, causing the maintenance of Cancer Initiating Cells and supporting the survival of senescent cells, especially in distal sites