Autophagy modulation as a potential therapeutic target for diverse diseases

Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
Nature Reviews Drug Discovery (Impact Factor: 41.91). 08/2012; 11(9):709-30. DOI: 10.1038/nrd3802
Source: PubMed


Autophagy is an essential, conserved lysosomal degradation pathway that controls the quality of the cytoplasm by eliminating protein aggregates and damaged organelles. It begins when double-membraned autophagosomes engulf portions of the cytoplasm, which is followed by fusion of these vesicles with lysosomes and degradation of the autophagic contents. In addition to its vital homeostatic role, this degradation pathway is involved in various human disorders, including metabolic conditions, neurodegenerative diseases, cancers and infectious diseases. This article provides an overview of the mechanisms and regulation of autophagy, the role of this pathway in disease and strategies for therapeutic modulation.

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Available from: David C Rubinsztein
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    • "It occurs at low levels in virtually all cells but is up-regulated upon starvation or other stressful stimuli to produce nutrients for cells and maintain cellular homeostasis. Dysfunction of autophagy is associated with multiple developmental defects and diseases, such as cancer, neurodegeneration, and heart diseases (Levine and Kroemer, 2008; Rubinsztein et al., 2012). There are three types of autophagy for delivering cytoplasmic contents to lysosomes and macroautophagy (hereafter referred to as autophagy) is the major autophagic mechanism in eukaryotic cells. "
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    ABSTRACT: Autophagy is a central lysosomal degradation pathway required for maintaining cellular homeostasis and its dysfunction is associated with numerous human diseases. To identify players in autophagy, we tested ∼1200 chemically induced mutations on the X-chromosome in Drosophila fat body clones and discovered that shibire (shi) plays an essential role in starvation-induced autophagy. Shi encodes a dynamin protein required for fission of clathrin-coated vesicles from the plasma membrane during endocytosis. We showed that Shi is dispensable for autophagy initiation and autophagosome‒lysosome fusion, but required for lysosomal/autolysosomal acidification. We also showed that other endocytic core machinery components like clathrin and AP2 play similar but not identical roles in regulating autophagy and lysosomal function as dynamin. Previous studies suggested that dynamin directly regulates autophagosome formation and autophagic lysosome reformation (ALR) through its excision activity. Here, we provide evidence that dynamin also regulates autophagy indirectly by regulating lysosomal function.
    Full-text · Article · Nov 2015 · Journal of Genetics and Genomics
    • "UPR signaling basically favors cell survival by ameliorating the equilibrium between protein loads and folding magnitude in the ER [13]. Apart from the HSR and UPR, eukaryotic cells employ autophagy, an evolutionary diverse, highly controlled, and orchestrated process, as an alternate defense mechanism to protect against the adverse effects of stress [14]. Autophagy is known as a double-edged sword due to its controversial protective or detrimental role, and is primarily associated Life Sciences 142 (2015) 36–48 ⁎ Corresponding author at: Department of Biotechnology, College of Engineering, Daegu "
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    ABSTRACT: Aims: Cells possess multiple methods for counteracting the deleterious consequences of stress induced by physical and chemical stimuli. Heat stress causes variations in the cellular environment, leading to cellular morbidity or mortality. Natural compounds that contain phenolic antioxidants, offer various therapeutic and biological activities. Vitexin, a natural flavonoid, has been reported to treat various pathologies due to its multifaceted effects. Herein, we investigated the therapeutic efficacy of vitexin and its underlying mechanism against heat stress in human lung epithelial cells. Main methods: Effect of vitexin on the expression of molecular chaperones, antioxidant enzymes, mitogen activated protein kinases (MAPKs), endoplasmic reticulum (ER)-stress and autophagy were measured by immunoblotting. qRT-PCR and EMSA was performed for Hsp90 expression and HSF-1 binding affinity. Cell viability was assessed by MTT and LDH assay. Detection of autophagy was confirmed by acridine orange staining. Role of Hsp90 inhibition on signaling pathways was elucidated by using specific chemical inhibitor, radicicol. Key findings: Whereas hyperthermia reduced cell viability, result of MTT and LDH assay showed that vitexin pre-treatment enhanced cell viability after heat stress. EMSA analysis shows DNA binding affinity of HSF-1 during heat stress. Vitexin upregulated Hsp90 expression, subsequently activating ER-stress induced autophagy. Modulation of MAPKs expression and fluorescence image analysis showed vacuole accumulation, indicating autophagic flux in cells. Hsp90 inhibition reversed the effect of vitexin and activates the apoptosis pathway. Significance: Our data suggest that vitexin can protect against hyperthermic cellular injury by induction of Hsp90 expression, antioxidant activity and MAPKs via ER stress-induced autophagy.
    No preview · Article · Oct 2015 · Life sciences
    • "Macroautophagy is, together with the proteasome system, one of the two major pathways responsible for the catabolism of cellular components. It is an evolutionary conserved process that takes place at baseline levels in most cells, predominantly exerting cytoprotective effects by removing damaged organelles and protein aggregates in order to maintain cellular homeostasis [1] [2]. "
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    ABSTRACT: Autophagy is a highly dynamic, evolutionary conserved cellular homeostatic process that occurs at baseline levels in most cells. It exerts predominantly cytoprotective effects by removing damaged organelles and protein aggregates. In cancer, however, autophagy acts as both a tumor suppressor by preventing ROS-induced tumorigenesis and as a tumor inducer by providing nutrients to tumor cells under hypoxic, low-energy conditions and protecting them against therapeutically induced stress. Pancreatic Ductal Adenocarcinoma is an extremely lethal and aggressive neoplasm with a 5 year-survival rate between 1% and 5%. One of the most important factors affecting its poor prognosis is its high resistance to most of the existing chemotherapeutic regimens. The role of autophagy in PDAC has been investigated by different research groups and the results are quite divergent; some research lines point at autophagy as a tumor promoting mechanism, whereas other studies assign oncosuppressive functions to it. Nevertheless, several distinct preclinical studies and clinical trials have evaluated the efficacy of both autophagy inducers and autophagy inhibitors as therapeutic compounds against PDAC, many of them providing promising results. Although a better understanding of the complexity of autophagy is needed, the modulation of this process opens new opportunities for prognostic and therapeutic purposes.
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