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      Microgravity induces autophagy via mitochondrial dysfunction in human Hodgkin’s lymphoma cells

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          Abstract

          Gravitational forces can impose physical stresses on the human body as it functions to maintain homeostasis. It has been reported that astronauts exposed to microgravity experience altered biological functions and many subsequent studies on the effects of microgravity have therefore been conducted. However, the anticancer mechanisms of simulated microgravity remain unclear. We previously showed that the proliferation of human Hodgkin’s lymphoma (HL) cells was inhibited when these cells were cultured in time-averaged simulated microgravity (taSMG). In the present study, we investigated whether taSMG produced an anticancer effect. Exposure of human HL cells to taSMG for 2 days increased their reactive oxygen species (ROS) production and NADPH oxidase family gene expression, while mitochondrial mass, ATPase, ATP synthase, and intracellular ATP levels were decreased. Furthermore, human HL cells exposed to taSMG underwent autophagy via AMPK/Akt/mTOR and MAPK pathway modulation; such autophagy was inhibited by the ROS scavenger N-acetylcysteine (NAC). These results suggest an innovative therapeutic approach to HL that is markedly different from conventional chemotherapy and radiotherapy.

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          Most cited references52

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          Autophagosome formation: core machinery and adaptations.

          Eukaryotic cells employ autophagy to degrade damaged or obsolete organelles and proteins. Central to this process is the formation of autophagosomes, double-membrane vesicles responsible for delivering cytoplasmic material to lysosomes. In the past decade many autophagy-related genes, ATG, have been identified that are required for selective and/or nonselective autophagic functions. In all types of autophagy, a core molecular machinery has a critical role in forming sequestering vesicles, the autophagosome, which is the hallmark morphological feature of this dynamic process. Additional components allow autophagy to adapt to the changing needs of the cell.
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            LKB1 and AMP-activated protein kinase control of mTOR signalling and growth.

            R J Shaw (2009)
            The AMP-activated serine/threonine protein kinase (AMPK) is a sensor of cellular energy status found in all eukaryotes that is activated under conditions of low intracellular ATP following stresses such as nutrient deprivation or hypoxia. In the past 5 years, work from a large number of laboratories has revealed that one of the major downstream signalling pathways regulated by AMPK is the mammalian target-of-rapamycin [mammalian target of rapamycin (mTOR) pathway]. Interestingly, like AMPK, the mTOR serine/threonine kinase plays key roles not only in growth control and cell proliferation but also in metabolism. Recent work has revealed that across eukaryotes mTOR orthologues are found in two biochemically distinct complexes and only one of those complexes (mTORC1 in mammals) is acutely sensitive to rapamycin and regulated by nutrients and AMPK. Many details of the molecular mechanism by which AMPK inhibits mTORC1 signalling have also been decoded in the past 5 years. AMPK directly phosphorylates at least two proteins to induce rapid suppression of mTORC1 activity, the TSC2 tumour suppressor and the critical mTORC1 binding subunit raptor. Here we explore the molecular connections between AMPK and mTOR signalling pathways and examine the physiological processes in which AMPK regulation of mTOR is critical for growth or metabolic control. The functional conservation of AMPK and TOR in all eukaryotes, and the sequence conservation around the AMPK phosphorylation sites in raptor across all eukaryotes examined suggest that this represents a fundamental cell growth module connecting nutrient status to the cell growth machinery. These findings have broad implications for the control of cell growth by nutrients in a number of cellular and organismal contexts.
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              Interplay between ROS and autophagy in cancer cells, from tumor initiation to cancer therapy

              Cancer formation is a complex and highly regulated multi-step process which is highly dependent of its environment, from the tissue to the patient. This complexity implies the development of specific treatments adapted to each type of tumor. The initial step of cancer formation requires the transformation of a healthy cell to a cancer cell, a process regulated by multiple intracellular and extracellular stimuli. The further steps, from the anarchic proliferation of cancer cells to form a primary tumor to the migration of cancer cells to distant organs to form metastasis, are also highly dependent of the tumor environment but of intracellular molecules and pathways as well. In this review, we will focus on the regulatory role of reactive oxygen species (ROS) and autophagy levels during the course of cancer development, from cellular transformation to the formation of metastasis. These data will allow us to discuss the potential of this molecule or pathway as putative future therapeutic targets.
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                Author and article information

                Contributors
                sungwan@snu.ac.kr
                sangkyu@snu.ac.kr
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                2 October 2018
                2 October 2018
                2018
                : 8
                : 14646
                Affiliations
                [1 ]ISNI 0000 0004 0470 5905, GRID grid.31501.36, Department of Pharmacology and Biomedical Sciences, , Seoul National University College of Medicine, ; Seoul, 03080 Republic of Korea
                [2 ]ISNI 0000 0004 0470 5905, GRID grid.31501.36, Biomedical Science Project (BK21PLUS), , Seoul National University College of Medicine, ; Seoul, 03080 Republic of Korea
                [3 ]ISNI 0000 0004 0470 5905, GRID grid.31501.36, Department of Biomedical Engineering, , Seoul National University College of Medicine, ; Seoul, 03080 Republic of Korea
                [4 ]ISNI 0000 0004 0470 5905, GRID grid.31501.36, Institute of Medical and Biological Engineering, Medical Research Center, , Seoul National University College of Medicine, ; Seoul, 03080 Republic of Korea
                [5 ]ISNI 0000 0004 0470 5905, GRID grid.31501.36, Ischemic/Hypoxic Disease Institute, , and Seoul National University College of Medicine, ; Seoul, 03080 Republic of Korea
                [6 ]ISNI 0000 0004 0470 5905, GRID grid.31501.36, Neuro-Immune Information Storage Network Research Center, , Seoul National University College of Medicine, ; Seoul, 03080 Republic of Korea
                [7 ]ISNI 0000 0004 0470 5905, GRID grid.31501.36, Interdisciplinary Program for Bioengineering, Graduate School, , Seoul National University, ; Seoul, 08826 Korea
                [8 ]ISNI 0000 0001 2218 7142, GRID grid.255166.3, Department of Biological Science, , Dong-A University, ; Busan, 49315 Republic of Korea
                Author information
                http://orcid.org/0000-0003-1547-2804
                http://orcid.org/0000-0002-9318-849X
                Article
                32965
                10.1038/s41598-018-32965-3
                6168562
                30279524
                3aae574d-2122-4e21-acd3-9a934b042385
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 20 March 2018
                : 12 September 2018
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100003716, Korea Basic Science Institute (KBSI);
                Award ID: 2016R1D1A1B03931766
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100003725, National Research Foundation of Korea (NRF);
                Award ID: 2015M1A3A3A02012636
                Award ID: 2014R1A2A1A11053203
                Award ID: 2017R1A2B2006839
                Award Recipient :
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