Autophagy and autophagy-related proteins in cancer

Abstract

Autophagy, as a type II programmed cell death, plays crucial roles with autophagy-related (ATG) proteins in cancer. Up to now, the dual role of autophagy both in cancer progression and inhibition remains controversial, in which the numerous ATG proteins and their core complexes including ULK1/2 kinase core complex, autophagy-specific class III PI3K complex, ATG9A trafficking system, ATG12 and LC3 ubiquitin-like conjugation systems, give multiple activities of autophagy pathway and are involved in autophagy initiation, nucleation, elongation, maturation, fusion and degradation. Autophagy plays a dynamic tumor-suppressive or tumor-promoting role in different contexts and stages of cancer development. In the early tumorigenesis, autophagy, as a survival pathway and quality-control mechanism, prevents tumor initiation and suppresses cancer progression. Once the tumors progress to late stage and are established and subjected to the environmental stresses, autophagy, as a dynamic degradation and recycling system, contributes to the survival and growth of the established tumors and promotes aggressiveness of the cancers by facilitating metastasis. This indicates that regulation of autophagy can be used as effective interventional strategies for cancer therapy.

Keywords: Autophagy; Autophagy-related proteins; Cancer promotor; Cancer suppressor; Cancer therapy.

Fig. 1

Schematic overview of autophagy. a Initiation, activation of ULK1 complex and multiple ATG proteins are engaged and localized to PAS. b Nucleation, ATG proteins and lipids are recruited to form phagophore; Elongation, cytoplasm and organelles are wrapped and engulfed during elongation of the phagophore; Maturation, completion and transport of the autophagosome. c Fusion, docking and fusion between autophagosome and lysosome. d Degradation, degradation of the cargos inside the autolysosome. e The ULK1 kinase core complex including ULK1, ATG13, FIP200, and ATG101. f The class III PI3K complex I including Beclin1, VPS34, VPS15, and ATG14L. g The ATG9A/ATG2-WIPI1/2 trafficking system including ATG9A, ATG2, and WIPI1/2. h The ATG12-conjugation system including ATG12, ATG7, ATG10, ATG5, and ATG16L. i The LC3-conjugation system including ProLC3, ATG4, LC3-I, ATG7, ATG3, and LC3-II (LC3-I/PE)

Fig. 2

Dual role of autophagy in tumorigenesis. Tumorigenesis begins with an oncogene mutation in the epithelial cell that makes the cell more likely to divide. The genetically altered or abnormal cells and its descendants grow and divide uncontrolled and rapidly at Hyperplasia stage. At Dysplasia stage, the overgrowing cells change their original form and behavior, have increased growth potential, and consist of more immature cells than mature. In situ cancer, the cells grow rapidly, but do not go into the process of maturation, have lost their tissue identity, and grow without regulation. In the malignant tumor (invasive cancer), the overgrowing cells invade neighboring areas and blood circulation systems from the primary tumor site by rupturing basal membrane. Metastases occur when cancer cells reach to the distant parts through lymphatic system and blood circulation. Autophagy plays dual roles during tumorigenesis including tumor-suppressing role during the early stage and cancer promoting role during the late stage