Beyond self‑eating: Emerging autophagy‑independent functions for the autophagy molecules in cancer (Review)

Abstract

Autophagy is a conserved catabolic process that controls organelle quality, removes misfolded or abnormally aggregated proteins and is part of the defense mechanisms against intracellular pathogens. Autophagy contributes to the suppression of tumor initiation by promoting genome stability, cellular integrity, redox balance and proteostasis. On the other hand, once a tumor is established, autophagy can support cancer cell survival and promote epithelial‑to‑mesenchymal transition. A growing number of molecules involved in autophagy have been identified. In addition to their key canonical activity, several of these molecules, such as ATG5, ATG12 and Beclin‑1, also exert autophagy‑independent functions in a variety of biological processes. The present review aimed to summarize autophagy‑independent functions of molecules of the autophagy machinery and how the activity of these molecules can influence signaling pathways that are deregulated in cancer progression.

Keywords: autophagy; autophagy‑independent; cancer; cancer progression; cell death; genome instability; metastasis; proliferation; survival.

Figure 1

Autophagic machinery. An overview of the autophagic process showing the signaling pathways that regulate autophagy and molecular circuitry involved in the key steps of phagolysosome formation: Nucleation, elongation, closure and fusion. Created with BioRender.com. ULK1, Unc-51-like autophagy-activating kinase 1; ATG, autophagy related genes; RB1CC1, RB1 Inducible Coiled-Coil 1; UVRAG, ultraviolet radiation resistance-associated gene; AMBRA1, autophagy and Beclin-1 regulator 1; ER, endoplasmic reticulum; PI3P, phosphatidylinositol-3-phosphate; SQSTM1, sequestrosome-1.

Figure 2

AMMs affecting genome stability and cell cycle progression. At G1/S checkpoint, AMBRA1 and ATG4B interact with cyclins controlling replication stress and genome instability whereas ATG7 interacts with p53 and promotes CDKN1A expression governing G1/S and G2/M checkpoints. A number of AMMs (UVRAG, ATG5 and Beclin-1) intervene in the processes of DNA repair involved in maintaining genome stability throughout the cell cycle. UVRAG interacts with DDB1, a component of the NER complex, to resolve DNA cross-links. ATG5, together with Mis18α, controls expression of MLH1 and impairs the mismatch repair system. UVRAG is involved in the response to double strand breaks by both NHEJ and HR. Beclin-1 interacts with UVRAG to regulate HR. Certain AMMs (Beclin-1, UVRAG, ATG5) interact with kinetochore structures that affect proper chromosomal segregation. Created with BioRender.com. AMM, autophagy machinery molecule; AMBRA1, autophagy and Beclin-1 regulator 1; ATG, Autophagy related genes; CDKN1A, Cyclin Dependent Kinase Inhibitor 1A; UVRAG, ultraviolet radiation resistance-associated gene; DDB1, Damage Specific DNA Binding Protein 1; NER, Nucleotide Excision Repair; Mis18α, MIS18 kinetochore Protein A; MLH1, MutL Homolog 1; NHEJ, Non-Homologous End Joining; HR, homologous Recombination; CEP63, Centrosomal Protein 63; ERCC2, Excision Repair Cross-Complementing Rodent Repair Deficiency, Complementation Group 2; XPC, Xeroderma Pigmentosum, Complementation Group C; DNA PK, Protein Kinase, DNA-Activated; ATM, Ataxia Telangiectasia Mutated; MMR, Mismatch Mediated Repair.

Figure 3

AMMs in cell death. Molecules that activate apoptosis, such as the caspase family, cleave AMMs, which act on mitochondrial homeostasis and apoptosis. ULK1 is involved in the control of cell death mediated by the TNFR. Upon activation TNFR forms a trimer and recruits a number of molecules in the intracellular compartment, including TRADD, TRAF2 and TRAF5, RIPK1 and cIAP1 and cIAP2. This core signaling complex leads to apoptotic cell death. ULK1 is also involved in necrosis, which is stimulated by increased ROS. Through its nuclear translocation, ULK1 potentiates activity of PARP1 and the PARylation of nuclear proteins. ROS are also responsible for the increase in LC3B production, which stimulates the expression of apoptotic molecules and the induction of anoikis. Created with BioRender.com. AMM, autophagy machinery molecules; ULK1, Unc-51-like autophagy-activating kinase 1; TNFR, Tumor Necrosis Factor Receptor; TRADD, tumor Necrosis Factor Receptor Type 1-Associated DEATH Domain Protein; TRAF, TNF Receptor Associated Factor; RIPK1, Receptor Interacting Serine/Threonine Kinase 1; cIAP, Cellular inhibitor of apoptosis protein; ROS, Reactive oxygen species; ATG, Autophagy related genes; AMBRA1, autophagy and Beclin-1 regulator 1; P, Phosphate; c-Ter, C-terminal.

Figure 4

Role of AMMs in invasiveness and tumor microenvironment. Beclin-1 acts independently of autophagy to control mediators of proliferation ERK, AKT and transcription factor STAT3. Beclin-1 is involved in the stability of epithelial junctions by interacting with α-catenin and E-cadherin. LC3 impairs actin cytoskeleton rearrangements by controlling RHO-GEF activation via interaction with AKP13 scaffold protein. The invasive behavior of cancer cells is supported by the upregulation of focal adhesions. ATG9B interacts with MYH9, stabilizing integrin B1 and talin 1, favoring the invasive behavior of cancer cells. ERK is activated by a number of AMMs when located on the autophagosomal membrane (LC3, ATG5, ATG12) upon colocalization with B1 integrin and c-Met. Cancer cells communicate with the tumor microenvironment by secretory autophagy to stimulate angiogenesis (releasing cathepsin B) or immune tolerance (via PAI1). Alternatively, cancer cells release exosomes containing mediators for invasion and metastasis (RAS, vimentin, β-catenin). Created with BioRender.com. AMM, autophagy machinery molecule; RHO-GEF, Rho family of GTPases; AKP13, A-Kinase Anchoring Protein 13; ATG, Autophagy-related genes; P, Phosphate; MYH9, myosin heavy chain 9; PAI1, plasminogenactivator-inhibitor; ATP6V1E1, ATPase H+ Transporting V1 Subunit E1.