Autophagy: Shedding Light on the Mechanisms and Multifaceted Roles in Cancers

Abstract

Autophagy, an evolutionarily conserved self-degradation catabolic mechanism, is crucial for recycling breakdown products and degrading intracellular components such as cytoplasmic organelles, macromolecules, and proteins in eukaryotes. The process, which can be selective or non-selective, involves the removal of specific ribosomes, protein aggregates, and organelles. Although the specific mechanisms governing various aspects of selective autophagy have not been fully understood, numerous studies have revealed that the dysregulation of autophagy-related genes significantly influences cellular homeostasis and contributes to a wide range of human diseases, particularly cancers, neurodegenerative disorders and inflammatory diseases. Notably, accumulating evidence highlights the complex, dual role of autophagy in cancer development. Thus, this review systematically summarizes the molecular mechanisms of autophagy and presents the latest research on its involvement in both pro- and anti-tumor progression. Furthermore, we discuss the role of autophagy in cancer development and summarize advancement in tumor therapies targeting autophagy.

Keywords: ATG 2; autophagy 1; cancers 3; cell death 4.

Figure 1

Major types of autophagy. During the process of microautophagy, the lysosomal membrane invaginates to envelop and degrade substrates within phagosomes, which are subsequently degraded within lysosomes. Different from microautophagy, macroautophagy entails the involvement of autophagosomes in the degradation process. During macroautophagy, damaged organelles and soluble macromolecules within the cytoplasm are enclosed by membranes originating from either the mitochondria or endoplasmic reticulum, leading to the formation of autophagosomes that are bounded by one or two membranes. The outer membrane of the autophagosome then merges with the lysosomal membrane, leading to the formation of an autolysosome. Within this structure, the materials designated for degradation through autophagy are broken down by various hydrolases. In the process of CMA, chaperone proteins identify and attach to soluble substrate proteins containing a particular amino acid sequence and then facilitate their transport to the lysosome. This process involves interacting with the LAMP2A receptor located on the lysosomal membrane. Once the substrate proteins reach the lysosome, they are broken down by lysosomal hydrolases.

Figure 2

Diagrammatic representation of the autophagy process in mammals. Initiation. Nutrient deficiency leads to the dissociation of ULK1/2 complex and various ATG proteins from MTORC1, resulting in the dephosphorylation of the ULK1/2 complex and autophagy induction. Nucleation. ULK1 enhances the phosphatidylinositol-3-kinase activity of a multiprotein complex comprised of BECN1, PIK3C3/VPS34, PIK3R4/VPS15, ATG14, and NRBF2 and furtherly drives the autophagosome nucleation. Notably, SH3GLB1, UVRAG, and AMBRA facilitate the nucleation of autophagosomes, while BCL2 and RUBCN inhibit this process. Elongation. After WIPI2 binds to PtdIns3P complex and is activated, the ATG12-ATG5-ATG16L1 complex and LC3 are recruited, contributing to the expansion of phagophores.

Figure 3

Several types of human cancers are linked to the dysregulation of autophagy. Autophagy is demonstrated to play a complex role in the occurrence and development of various human cancers, including lung cancer, breast cancer, esophageal cancer, colorectal cancer, prostate cancer, gastric cancer, liver cancer, thyroid cancer, cervical cancer, bladder cancer, hematologic malignancies, among others.