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      Targeting autophagy in cancer.

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          Abstract

          Autophagy is a mechanism by which cellular material is delivered to lysosomes for degradation, leading to the basal turnover of cell components and providing energy and macromolecular precursors. Autophagy has opposing, context-dependent roles in cancer, and interventions to both stimulate and inhibit autophagy have been proposed as cancer therapies. This has led to the therapeutic targeting of autophagy in cancer to be sometimes viewed as controversial. In this Review, we suggest a way forwards for the effective targeting of autophagy by understanding the context-dependent roles of autophagy and by capitalizing on modern approaches to clinical trial design.

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          The role of Atg proteins in autophagosome formation.

          Noboru Mizushima, Tamotsu Yoshimori, Yoshinori Ohsumi (2011)
          Macroautophagy is mediated by a unique organelle, the autophagosome, which encloses a portion of cytoplasm for delivery to the lysosome. Autophagosome formation is dynamically regulated by starvation and other stresses and involves complicated membrane reorganization. Since the discovery of yeast Atg-related proteins, autophagosome formation has been dissected at the molecular level. In this review we describe the molecular mechanism of autophagosome formation with particular focus on the function of Atg proteins and the long-standing discussion regarding the origin of the autophagosome membrane.
          Article 0 comments Cited 1122 times – based on 0 reviews     Review now
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            Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy

            Joseph D. Mancias, Xiaoxu Wang, Steven P. Gygi … (2014)
            Autophagy, the process by which proteins and organelles are sequestered in double-membrane structures called autophagosomes and delivered to lysosomes for degradation, is critical in diseases such as cancer and neurodegeneration 1,2 . Much of our understanding of this process has emerged from analysis of bulk cytoplasmic autophagy, but our understanding of how specific cargo including organelles, proteins, or intracellular pathogens are targeted for selective autophagy is limited 3 . We employed quantitative proteomics to identify a cohort of novel and known autophagosome-enriched proteins, including cargo receptors. Like known cargo receptors, NCOA4 was highly enriched in autophagosomes, and associated with ATG8 proteins that recruit cargo-receptor complexes into autophagosomes. Unbiased identification of NCOA4-associated proteins revealed ferritin heavy and light chains, components of an iron-filled cage structure that protects cells from reactive iron species 4 but is degraded via autophagy to release iron 5,6 through an unknown mechanism. We found that delivery of ferritin to lysosomes required NCOA4, and an inability of NCOA4-deficient cells to degrade ferritin leads to decreased bioavailable intracellular iron. This work identifies NCOA4 as a selective cargo receptor for autophagic turnover of ferritin (ferritinophagy) critical for iron homeostasis and provides a resource for further dissection of autophagosomal cargo-receptor connectivity.
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              Pancreatic cancers require autophagy for tumor growth.

              Shenghong Yang, Xiaoxu Wang, Gianmarco Contino … (2011)
              Macroautophagy (autophagy) is a regulated catabolic pathway to degrade cellular organelles and macromolecules. The role of autophagy in cancer is complex and may differ depending on tumor type or context. Here we show that pancreatic cancers have a distinct dependence on autophagy. Pancreatic cancer primary tumors and cell lines show elevated autophagy under basal conditions. Genetic or pharmacologic inhibition of autophagy leads to increased reactive oxygen species, elevated DNA damage, and a metabolic defect leading to decreased mitochondrial oxidative phosphorylation. Together, these ultimately result in significant growth suppression of pancreatic cancer cells in vitro. Most importantly, inhibition of autophagy by genetic means or chloroquine treatment leads to robust tumor regression and prolonged survival in pancreatic cancer xenografts and genetic mouse models. These results suggest that, unlike in other cancers where autophagy inhibition may synergize with chemotherapy or targeted agents by preventing the up-regulation of autophagy as a reactive survival mechanism, autophagy is actually required for tumorigenic growth of pancreatic cancers de novo, and drugs that inactivate this process may have a unique clinical utility in treating pancreatic cancers and other malignancies with a similar dependence on autophagy. As chloroquine and its derivatives are potent inhibitors of autophagy and have been used safely in human patients for decades for a variety of purposes, these results are immediately translatable to the treatment of pancreatic cancer patients, and provide a much needed, novel vantage point of attack.
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                Author and article information

                Journal
                Journal ID (iso-abbrev): Nat. Rev. Cancer
                Title: Nature reviews. Cancer
                Publisher: Springer Science and Business Media LLC
                ISSN (Electronic): 1474-1768
                ISSN (Print): 1474-175X
                Publication date (Electronic): September 2017
                Volume: 17
                Issue: 9
                Affiliations
                [1 ] Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
                [2 ] Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, Colorado 80045, USA.
                [3 ] Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
                Article
                Publisher Item ID: nrc.2017.53 Mid ID: NIHMS966579
                DOI: 10.1038/nrc.2017.53
                PMC ID: 5975367
                PubMed ID: 28751651
                SO-VID: aba37d8c-4b42-4dad-bdd8-fd8f90d5a42a
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