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      Etoposide Triggers Cellular Senescence by Inducing Multiple Centrosomes and Primary Cilia in Adrenocortical Tumor Cells

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          Abstract

          Etoposide (ETO) has been used in treating adrenocortical tumor (ACT) cells. Our previous study showed that ETO inhibits ACT cell growth. In the present study, we show that ETO treatment at IC50 (10 μM) inhibited ACT cell growth by inducing cellular senescence rather than apoptosis. Several markers of cellular senescence, including enlarged nuclei, activated senescence-associated β-galactosidase activity, elevated levels of p53 and p21, and down-regulation of Lamin B1, were observed. We further found that ETO induced multiple centrosomes. The inhibition of multiple centrosomes accomplished by treating cells with either roscovitine or centrinone or through the overexpression of NR5A1/SF-1 alleviated ETO-induced senescence, suggesting that ETO triggered senescence via multiple centrosomes. Primary cilia also played a role in ETO-induced senescence. In the mechanism, DNA-PK-Chk2 signaling was activated by ETO treatment; inhibition of this signaling cascade alleviated multiple ETO-induced centrosomes and primary cilia followed by reducing cellular senescence. In addition to DNA damage signaling, autophagy was also triggered by ETO treatment for centrosomal events and senescence. Importantly, the inactivation of DNA-PK-Chk2 signaling reduced ETO-triggered autophagy; however, the inhibition of autophagy did not affect DNA-PK-Chk2 activation. Thus, ETO activated the DNA-PK-Chk2 cascade to facilitate autophagy. The activated autophagy further induced multiple centrosomes and primary cilia followed by triggering senescence.

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          Autophagy: renovation of cells and tissues.

          Autophagy is the major intracellular degradation system by which cytoplasmic materials are delivered to and degraded in the lysosome. However, the purpose of autophagy is not the simple elimination of materials, but instead, autophagy serves as a dynamic recycling system that produces new building blocks and energy for cellular renovation and homeostasis. Here we provide a multidisciplinary review of our current understanding of autophagy's role in metabolic adaptation, intracellular quality control, and renovation during development and differentiation. We also explore how recent mouse models in combination with advances in human genetics are providing key insights into how the impairment or activation of autophagy contributes to pathogenesis of diverse diseases, from neurodegenerative diseases such as Parkinson disease to inflammatory disorders such as Crohn disease. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Autophagy: cellular and molecular mechanisms.

            Autophagy is a self-degradative process that is important for balancing sources of energy at critical times in development and in response to nutrient stress. Autophagy also plays a housekeeping role in removing misfolded or aggregated proteins, clearing damaged organelles, such as mitochondria, endoplasmic reticulum and peroxisomes, as well as eliminating intracellular pathogens. Thus, autophagy is generally thought of as a survival mechanism, although its deregulation has been linked to non-apoptotic cell death. Autophagy can be either non-selective or selective in the removal of specific organelles, ribosomes and protein aggregates, although the mechanisms regulating aspects of selective autophagy are not fully worked out. In addition to elimination of intracellular aggregates and damaged organelles, autophagy promotes cellular senescence and cell surface antigen presentation, protects against genome instability and prevents necrosis, giving it a key role in preventing diseases such as cancer, neurodegeneration, cardiomyopathy, diabetes, liver disease, autoimmune diseases and infections. This review summarizes the most up-to-date findings on how autophagy is executed and regulated at the molecular level and how its disruption can lead to disease. Copyright (c) 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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              Cellular signalling by primary cilia in development, organ function and disease

              Primary cilia project in a single copy from the surface of most vertebrate cell types; they detect and transmit extracellular cues to regulate diverse cellular processes during development and to maintain tissue homeostasis. The sensory capacity of primary cilia relies on the coordinated trafficking and temporal localization of specific receptors and associated signal transduction modules in the cilium. The canonical hedgehog (HH) pathway, for example, is a bona fide ciliary signalling system that regulates cell fate and self-renewal in development and tissue homeostasis. Specific receptors and associated signal transduction proteins can also localize to primary cilia in a cell type-dependent manner; available evidence suggests that the ciliary constellation of these proteins can temporally change to allow the cell to adapt to specific developmental and homeostatic cues. Consistent with important roles for primary cilia in signalling, mutations that lead to their dysfunction underlie a pleiotropic group of diseases and syndromic disorders termed ciliopathies, which affect many different tissues and organs of the body. In this review we highlight central mechanisms by which primary cilia coordinate HH, G-protein-coupled receptor, WNT, receptor tyrosine kinase and TGFβ/BMP signalling, and illustrate how defects in the balanced output of ciliary signalling events are coupled to developmental disorders and disease progression.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                11 June 2021
                June 2021
                : 10
                : 6
                : 1466
                Affiliations
                [1 ]Department of Biological Sciences and Technology, National University of Tainan, Tainan 700, Taiwan; tengyenni1968@ 123456gmail.com (Y.-N.T.); air840805@ 123456gmail.com (H.-C.C.)
                [2 ]Department of Physical Medicine and Rehabilitation, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
                [3 ]Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; yuyingchaoo@ 123456gmail.com (Y.-Y.C.); tomato4329@ 123456gmail.com (H.-L.C.)
                [4 ]Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
                [5 ]Department of Physical Medicine and Rehabilitation, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
                Author notes
                [* ]Correspondence: lwclwhab@ 123456ms8.hinet.net (W.-C.L.); b89609046@ 123456gmail.com (C.-Y.W.); Tel.: +886-6-2353535 (ext. 5240) (W.-C.L. & C.-Y.W.); Fax: +886-6-2093007 (W.-C.L. & C.-Y.W.)
                Author information
                https://orcid.org/0000-0002-9196-0802
                Article
                cells-10-01466
                10.3390/cells10061466
                8230646
                34208028
                5efec600-067b-46c7-857f-d257c64414b3
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 21 February 2021
                : 09 June 2021
                Categories
                Article

                etoposide,centrosome,primary cilia,senescence,autophagy,dna-pk,chk2
                etoposide, centrosome, primary cilia, senescence, autophagy, dna-pk, chk2

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