Autophagy Review Article Text

Department of molecular biology and biochemistry, rutgers university, piscataway, new jersey, usa. Address correspondence to: eileen white, rutgers cancer institute of new jersey, 195 little albany street, new brunswick, new jersey 08903, usa. Autophagy is a survival promoting pathway that captures, degrades, and recycles intracellular proteins and organelles in lysosomes. Autophagy preserves organelle function, prevents the toxic buildup of cellular waste products, and provides substrates to sustain metabolism in starvation.

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Although in some contexts autophagy suppresses tumorigenesis, in most contexts autophagy facilitates tumorigenesis. Cancers can upregulate autophagy to survive microenvironmental stress and to increase growth and aggressiveness. Mechanisms by which autophagy promotes cancer include suppressing induction of the p53 tumor suppressor protein and maintaining metabolic function of mitochondria. Efforts to inhibit autophagy to improve cancer therapy have thereby attracted great interest.

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Autophagy captures and degrades intracellular components such as proteins and organelles to sustain metabolism and homeostasis. Low levels of basal autophagy prevent the gradual accumulation of damaged proteins and organelles in tissues that is toxic over time thus, autophagy plays an important role in protein and organelle quality control 1 . Identification of the autophagy substrates that are deregulated in autophagy deficient cells and tissues is important to understand the biological role and tissue specificity of autophagy.

Determination of the global impact of autophagy on the cellular proteome would be a significant advance, as we are only beginning to understand the broad scope of autophagy substrates and the functional consequence of deregulating their degradation and recycling. Some tissues such as liver, brain, and muscle are particularly dependent on autophagy to prevent the buildup of damaged mitochondria and protein aggregates containing the autophagy substrate p62/sqstm1 p62 and ubiquitin 1 . Accumulation of defective mitochondria that results from impaired autophagy can perturb metabolism and generate oxidative stress 2 . Autophagy also mitigates er stress, and autophagy defects can produce accumulation of chaperone proteins that increase the unfolded protein burden 3.

The toxicity of autophagy defects in liver is partly ameliorated by deficiency in the autophagy substrate p62, but this is not the case for the brain 5. The recent revelation that autophagy is important for recycling iron complexed with ferritin through ferritinophagy may be critical for iron homeostasis in many tissues, potentially including brain 7 . The accumulation of, or imbalance in, levels of some cellular components caused by autophagy defects may be indirect. For example, lipid accumulation in autophagy deficient liver and some lung tumors can arise from defects in the autophagy of lipid droplets through lipophagy 8 or indirectly from defects in mitochondrial fatty acid oxidation fao that repress lipid catabolism 9 . These findings collectively demonstrate the broad effects of autophagy on cellular homeostasis at the level of substrate removal, maintenance of organelle function, and detoxification. Thus, autophagy dependence is tissue specific, not only for the general requirement for the level of autophagic activity, but also for the nature of the substrates that require autophagy mediated elimination or recycling. Acute autophagy induction is critical for yeast and normal mammalian cells and mammals to survive starvation, which is attributed to the recycling of intracellular components into metabolic pathways 2 .

Autophagy thereby functions to promote metabolic homeostasis and survival that is essential during nutrient deprivation. While it is generally appreciated that autophagy mediated degradation of intracellular proteins and organelles provides metabolic substrates during starvation, the exact substrates that are important and the metabolic pathways they support remain to be identified 2. The metabolic role for autophagy partly overlaps with the protein and organelle quality control function and further broadens the impact autophagy has on mammalian physiology and disease. The role of autophagy in normal cells and tissues is clearly complex and tissue dependent 1 . Autophagy deficiency is thought to contribute to the pathogenicity in many diseases including neurodegenerative diseases, liver disease, and aging 11 .

Autophagy has been reported to either inhibit or promote cancer cell proliferation or tumorigenesis in model systems, suggesting that the role of autophagy in cancer is context dependent 12 . It is worth exploring these mechanisms, as they may reveal insights into novel means for regulating cancer growth. This concept derived from early reports that the essential autophagy gene atg6/becn1 was monoallelically lost in 40% to 75% of human prostate, breast, and ovarian cancers 13 – 15 . Indeed, in certain cell based assays, autophagy suppression promotes cancer cell growth, and becn1 heterozygous mutant mice are prone to development of liver and lung tumors and lymphomas with long latency 16. In contrast, mosaic or liver specific autophagy deficiency through deletion of the essential autophagy genes atg5 or atg7 in mice produces only benign liver tumors 18 . These findings called into question the role of autophagy in tumor suppression in tissues other than liver and whether the potential role of becn1 in other cancer is autophagy related. The possibility that becn1 is a tumor suppressor gene based on its allelic loss is confounded by its location adjacent to breast and ovarian tumor suppressor breast cancer 1, early onset brca1 on human chromosome 17q21.

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Moreover, hereditary breast and ovarian cancer arises from missense mutations in brca1 with subsequent loss of the wild type allele that may or may not include deletion of becn1 19 . In genetically engineered mouse models gemms for hereditary breast cancer, allelic loss of becn1 promotes p53 activation and reduces tumorigenesis, which is the opposite result expected if becn1 is acting as a tumor suppressor 20 . Note that large scale genomic analysis of human cancers to date has failed to identify recurrent mutations in becn1 or other essential autophagy genes 21. The mutational status of becn1 was assessed in the human tumor sequencing data from 10,0 tumors with matched normal tissue in the cancer genome atlas tcga data.nci.nih.gov/tcga/ and other databases. Were found in breast and ovarian cancers, consistent with brca1 loss being the driver mutation in these cancers 19 .

Furthermore, there was no evidence for statistically significant recurrent missense mutations in becn1 in breast or ovarian cancers or mutation or loss in any other cancer, including prostate cancer 19 . Thus, loss of becn1 in human cancers cannot be disassociated from the loss of brca1. Indicating that becn1 is not a tumor suppressor in most human cancers 19 . There may, however, be tumor types or subtypes that have not yet been sufficiently characterized at the genomic level, such as hepatomas, where autophagy genes may be mutated and where their loss of function may promote cancer.