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      Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles.

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          Abstract

          Autophagy is central to the maintenance of organismal homeostasis in both physiological and pathological situations. Accordingly, alterations in autophagy have been linked to clinically relevant conditions as diverse as cancer, neurodegeneration and cardiac disorders. Throughout the past decade, autophagy has attracted considerable attention as a target for the development of novel therapeutics. However, such efforts have not yet generated clinically viable interventions. In this Review, we discuss the therapeutic potential of autophagy modulators, analyse the obstacles that have limited their development and propose strategies that may unlock the full therapeutic potential of autophagy modulation in the clinic.

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          Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009.

          G Kroemer, L Galluzzi, P Vandenabeele … (2009)
          Different types of cell death are often defined by morphological criteria, without a clear reference to precise biochemical mechanisms. The Nomenclature Committee on Cell Death (NCCD) proposes unified criteria for the definition of cell death and of its different morphologies, while formulating several caveats against the misuse of words and concepts that slow down progress in the area of cell death research. Authors, reviewers and editors of scientific periodicals are invited to abandon expressions like 'percentage apoptosis' and to replace them with more accurate descriptions of the biochemical and cellular parameters that are actually measured. Moreover, at the present stage, it should be accepted that caspase-independent mechanisms can cooperate with (or substitute for) caspases in the execution of lethal signaling pathways and that 'autophagic cell death' is a type of cell death occurring together with (but not necessarily by) autophagic vacuolization. This study details the 2009 recommendations of the NCCD on the use of cell death-related terminology including 'entosis', 'mitotic catastrophe', 'necrosis', 'necroptosis' and 'pyroptosis'.
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            Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor.

            Zhenyu Yue, Shengkan Jin, Chingwen Yang … (2003)
            The biochemical properties of beclin 1 suggest a role in two fundamentally important cell biological pathways: autophagy and apoptosis. We show here that beclin 1-/- mutant mice die early in embryogenesis and beclin 1+/- mutant mice suffer from a high incidence of spontaneous tumors. These tumors continue to express wild-type beclin 1 mRNA and protein, establishing that beclin 1 is a haploinsufficient tumor suppressor gene. Beclin 1-/- embryonic stem cells have a severely altered autophagic response, whereas their apoptotic response to serum withdrawal or UV light is normal. These results demonstrate that beclin 1 is a critical component of mammalian autophagy and establish a role for autophagy in tumor suppression. They both provide a biological explanation for recent evidence implicating beclin 1 in human cancer and suggest that mutations in other genes operating in this pathway may contribute to tumor formation through deregulation of autophagy.
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              Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis.

              Congcong He, Michael C. Bassik, Viviana Moresi … (2012)
              Exercise has beneficial effects on human health, including protection against metabolic disorders such as diabetes. However, the cellular mechanisms underlying these effects are incompletely understood. The lysosomal degradation pathway, autophagy, is an intracellular recycling system that functions during basal conditions in organelle and protein quality control. During stress, increased levels of autophagy permit cells to adapt to changing nutritional and energy demands through protein catabolism. Moreover, in animal models, autophagy protects against diseases such as cancer, neurodegenerative disorders, infections, inflammatory diseases, ageing and insulin resistance. Here we show that acute exercise induces autophagy in skeletal and cardiac muscle of fed mice. To investigate the role of exercise-mediated autophagy in vivo, we generated mutant mice that show normal levels of basal autophagy but are deficient in stimulus (exercise- or starvation)-induced autophagy. These mice (termed BCL2 AAA mice) contain knock-in mutations in BCL2 phosphorylation sites (Thr69Ala, Ser70Ala and Ser84Ala) that prevent stimulus-induced disruption of the BCL2-beclin-1 complex and autophagy activation. BCL2 AAA mice show decreased endurance and altered glucose metabolism during acute exercise, as well as impaired chronic exercise-mediated protection against high-fat-diet-induced glucose intolerance. Thus, exercise induces autophagy, BCL2 is a crucial regulator of exercise- (and starvation)-induced autophagy in vivo, and autophagy induction may contribute to the beneficial metabolic effects of exercise.
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                Author and article information

                Journal
                Journal ID (iso-abbrev): Nat Rev Drug Discov
                Title: Nature reviews. Drug discovery
                Publisher: Springer Nature
                ISSN (Electronic): 1474-1784
                ISSN (Print): 1474-1776
                Publication date (Electronic): May 19 2017
                Affiliations
                [1 ] Department of Radiation Oncology, Weill Cornell Medical College, New York, New York 10065, USA.
                [2 ] Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris 75006, France.
                [3 ] Université Pierre et Marie Curie/Paris VI, Paris 75006, France.
                [4 ] Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris 75006, France.
                [5 ] INSERM, U1138, Paris 75006, France.
                [6 ] Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif 94805, France.
                [7 ] Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
                [8 ] Howard Hughes Medical Institute, Dallas, Texas 75390, USA.
                [9 ] St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
                [10 ] Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm 17176, Sweden.
                [11 ] Pôle de Biologie, Hopitâl Européen George Pompidou (AP-HP), Paris 75015, France.
                Article
                Publisher Item ID: nrd.2017.22
                DOI: 10.1038/nrd.2017.22
                PubMed ID: 28529316
                SO-VID: f31dda76-f911-4583-96fb-8bcd0968be19
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