Autophagy: a necessary evil in cancer and inflammation

Abstract

Autophagy, a highly regulated cellular process, assumes a dual role in the context of cancer. On the one hand, it functions as a crucial homeostatic pathway, responsible for degrading malfunctioning molecules and organelles, thereby maintaining cellular health. On the other hand, its involvement in cancer development and regression is multifaceted, contingent upon a myriad of factors. This review meticulously examines the intricacies of autophagy, from its molecular machinery orchestrated by Autophagy-Related Genes (ATG) initially discovered in yeast to the various modes of autophagy operative within cells. Beyond its foundational role in cellular maintenance, autophagy reveals context-specific functions in processes like angiogenesis and inflammation. Our analysis delves into how autophagy-related factors directly impact inflammation, underscoring their profound implications for cancer dynamics. Additionally, we extend our inquiry to explore autophagy's associations with cardiovascular conditions, neurodegenerative disorders, and autoimmune diseases, illuminating the broader medical relevance of this process. Furthermore, this review elucidates how autophagy contributes to sustaining hallmark cancer features, including stem cell maintenance, proliferation, angiogenesis, metastasis, and metabolic reprogramming. Autophagy emerges as a pivotal process that necessitates careful consideration in cancer treatment strategies. To this end, we investigate innovative approaches, ranging from enzyme-based therapies to MTOR inhibitors, lysosomal blockers, and nanoparticle-enabled interventions, all aimed at optimizing cancer treatment outcomes by targeting autophagy pathways. In summary, this comprehensive review provides a nuanced perspective on the intricate and context-dependent role of autophagy in cancer biology. Our exploration not only deepens our understanding of this fundamental process but also highlights its potential as a therapeutic target. By unraveling the complex interplay between autophagy and cancer, we pave the way for more precise and effective cancer treatments, promising better outcomes for patients.

Keywords: Angiogenesis; Autophagy; Cancer; Endoplasmic reticulum; Inflammation; Nanoparticle.

Fig. 1

“Diverse Forms of Autophagy and Cargo Selectivity”. This figure illustrates the various forms of autophagy, each with distinct functions and mechanisms. The selectivity of autophagic cargos is regulated by specific cargo receptors or adaptors, which recognize and sequester target substrates for degradation

Fig. 2

The multistep process of autophagy and its regulatory components. Autophagy involves several stages: initiation, nucleation, elongation, fusion, and degradation. AMPK and mTOR serve as major modulators of autophagy, while ATGs (autophagy-related genes) are closely associated with the process. During initiation, ULK (Unc-51-like kinase) phosphorylates ATG13 and FIP200, leading to their activation. In nucleation, ULK1 phosphorylates Ambra1, which interacts with Beclin-1. Beclin-1 then forms a complex with other proteins, called the PI3KC3 complex. The phagophore is formed, enclosing cytoplasmic components during the elongation stage. The phagophore expands to form autophagosomes. Subsequently, autophagosomes fuse with lysosomes, forming autolysosomes. Within the autolysosomes, various cytoplasmic components are degraded by enzymes. AMPK AMP-activated protein kinase, mTOR mammalian target of rapamycin, ULK Unc-51-like kinase, FIP200 Focal adhesion kinase family interacting protein of 200-kDa, PI3KC3 Class III phosphatidylinositol 3-kinase. (The image legend clarifies that autophagic cargos are represented by purple and green colors, while red and yellow colors symbolize lysosomal enzymes. In the lower corner of the image, it is explained that the light green color corresponds to LC3.)

Fig. 3

“The Intricate Interplay of Autophagy, Inflammasome Activation, and Cancer”.The figure illustrate the intricate relationship between autophagy, inflammasome activation, and cancer. Dysfunctional autophagy and mitochondrial impairment culminate in heightened oxidative stress, triggering autophagic cell death, inflammasome activation. Elevated levels of mitochondrial reactive oxygen species (ROS) further promote oncogenesis, chemoresistance, and metastasis. Autophagy serves a dual role in cancer and inflammation, both supporting tumor growth and orchestrating immune responses. This reciprocal interaction between cancer, inflammation, and autophagy involves the activation of oncogenic pathways, metabolic alterations, and the modulation of the tumor microenvironment. This complex crosstalk holds significant implications for disease progression and potential therapeutic strategies

Fig. 4

Autophagy and its role in different aspects of the immune system. Autophagy serves as a crucial mechanism in various facets of the immune system, contributing to immune cell development, function, and regulation, while also playing a pivotal role in host defense against intracellular pathogens and maintaining immune system balance

Fig. 5

Crosstalk between autophagy, inflammation, and tumorigenesis in the context of RAS-mutated and tumor cells. This diagram illustrates the intricate interplay between autophagy, inflammation, and tumorigenesis, with a particular focus on the role of high-mobility group protein B1 (HMGB1), interleukin-6 (IL-6), and interleukin-8 (IL-8) in promoting increased invasion and tumorigenesis. Additionally, these factors contribute to heightened inflammation, a phenomenon prominently observed in RAS-mutated cells and various tumor cell types