Role of autophagy in cancer prevention - PubMed (original) (raw)

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Role of autophagy in cancer prevention

Hsin-Yi Chen et al. Cancer Prev Res (Phila). 2011 Jul.

Abstract

Macroautophagy (autophagy hereafter) is a catabolic process by which cells degrade intracellular components in lysosomes. This cellular garbage disposal and intracellular recycling system maintains cellular homeostasis by eliminating superfluous or damaged proteins and organelles and invading microbes and by providing substrates for energy generation and biosynthesis in stress. Autophagy thus promotes the health of cells and animals and is critical for the development, differentiation, and maintenance of cell function and for the host defense against pathogens. Deregulation of autophagy is linked to susceptibility to various disorders including degenerative diseases, metabolic syndrome, aging, infectious diseases, and cancer. Autophagic activity emerges as a critical factor in the development and progression of diseases that are associated with increased cancer risk as well as in different stages of cancer. Given that cancer is a complex process and autophagy exerts its effects in multiple ways, the role of autophagy in tumorigenesis is context-dependent. As a cytoprotective survival pathway, autophagy prevents chronic tissue damage that can lead to cancer initiation and progression. In this setting, stimulation or restoration of autophagy may prevent cancer. In contrast, once cancer occurs, many cancer cells upregulate basal autophagy and utilize autophagy to enhance fitness and survive in the hostile tumor microenvironment. These findings revealed the concept that aggressive cancers can be addicted to autophagy for survival. In this setting, autophagy inhibition is a therapeutic strategy for established cancers.

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Figures

Figure 1

Figure 1. Machinery and small molecule modulators of autophagy

The events of autophagosome formation- nucleation, expansion and maturation are depicted along with molecular machinery that regulates this process. The major negative regulator of autophagy, mTORC1, which integrates stimuli including availability of nutrients or growth factors, energy depletion or hypoxia, is also shown. Drugable protein targets are highlighted with striated outlines. Green or Red boxes indicate autophagy stimulators or inhibitors respectively. Question marks represent inhibitors aiming at potential targets, the kinase Ulk1, the cysteine protease Atg4 and the E1-like ubiquitination enzyme Atg7. AMPK: AMP-activated protein kinase. PE: phosphatidylethanolamine. IP3: inositol-1,4,5-triphosphate. IP3R: inositol-1,4,5-triphosphate receptor. CBZ: carbamazepine. HCQ: hydroxychloroquine.

Figure 2

Figure 2. Role of autophagic regulation of p62 in cell signaling

Stress upregulates autophagy and also induces the accumulation of the autophagic cargo receptor protein p62. Autophagy regulates p62 turnover and its protein levels in cells (denoted by an asterisk). Domains of p62 are depicted diagrammatically. PB1: Phox and Bem1p-1 oligomerization domain. ZZ: zinc finger. TBS: TRAF6-binding sequence. LIR: LC3-interacting region. KIR: Keap1-interacting region. UBA: ubiquitin-associated domain. Numbers represent the corresponding amino acid positions in mouse p62. NLS: nuclear localization signal. NES: nuclear export signal (40, 43, 76). Brown arrows indicate p62-protein interactions. The dash indicates a putative interaction between p62 and ERK (77). Accumulation of p62 activates Nrf2, while p62 itself is a transcriptional target of Nrf2, creating a positive feedback loop (45). Green or red depicts signals occurring when p62 loses or gains function, respectively. The dashed green line shows a putative role of obesity in tumorigenesis (see Fig. 3). The dashed red line shows a putative consequence of hyperactive Nrf2.

Figure 3

Figure 3. Role of autophagy in health and disease progression

Autophagy is required for cellular and organismal heath and is involved in the pathogenesis of a variety of diseases. Disorders are shown in blue. Lines with an arrowhead or a cross short line represent positive or negative regulation of the pathway, respectively. Bold or gray lines represent pathways upregulated or downregulated respectively during lipid homeostasis collapse. The dashed line depicts flux of fatty acids from adipocytes to liver. The asterisk indicates the abnormal deposit of fatty acids in liver when lipid homeostasis is disrupted. The question mark denotes a putative regulation. Yellow shading shows where autophagy is involved in the regulation of lipid homeostasis. Red shading shows inflammation, which promotes tumorigenesis and is suppressed by autophagy. HFD: high-fat diet.

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