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      Molecular Switch Role of Akt in Polygonatum odoratum Lectin-Induced Apoptosis and Autophagy in Human Non-Small Cell Lung Cancer A549 Cells

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          Abstract

          Polygonatum odoratum lectin (POL), isolated from traditional Chinese medicine herb (Mill.) Druce, has drawn rising attention due to its wide biological activities. In the present study, anti-tumor effects, including apoptosis- and autophagy-inducing properties of POL, were determined by a series of cell biology methods such as MTT, cellular morphology observation, flow cytometry, immunoblotting. Herein, we found that POL could simultaneously induce apoptosis and autophagy in human non-small cell lung cancer A549 cells. POL initiated apoptosis through inhibiting Akt-NF-κB pathway, while POL triggered autophagy via suppressing Akt-mTOR pathway, suggesting the molecular switch role of Akt in regulating between POL-induced apoptosis and autophagy. Moreover, ROS was involved in POL-induced inhibition of Akt expression, and might therefore mediate both apoptosis and autophagy in A549 cells. In addition, POL displayed no significant cytotoxicity toward normal human embryonic lung fibroblast HELF cells. Due to the anti-tumor activities, POL might become a potent anti-cancer drug in future therapy, which might pave the way for exploring GNA-related lectins into effective drugs in cancer treatment.

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          Most cited references23

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          Death by design: apoptosis, necrosis and autophagy.

          Apoptosis is the principal mechanism by which cells are physiologically eliminated in metazoan organisms. During apoptotic death, cells are neatly carved up by caspases and packaged into apoptotic bodies as a mechanism to avoid immune activation. Recently, necrosis, once thought of as simply a passive, unorganized way to die, has emerged as an alternate form of programmed cell death whose activation might have important biological consequences, including the induction of an inflammatory response. Autophagy has also been suggested as a possible mechanism for non-apoptotic death despite evidence from many species that autophagy represents a survival strategy in times of stress. Recent advances have helped to define the function of and mechanism for programmed necrosis and the role of autophagy in cell survival and suicide.
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            Apoptosis and autophagy: regulatory connections between two supposedly different processes.

            Apoptosis and autophagy are genetically-regulated, evolutionarily-conserved processes that regulate cell fate. Both apoptosis and autophagy are important in development and normal physiology and in a wide range of diseases. Recent studies show that despite the marked differences between these two processes, their regulation is intimately connected and the same regulators can sometimes control both apoptosis and autophagy. In this review, I discuss some of these findings, which provide possible molecular mechanisms for crosstalk between apoptosis and autophagy and suggest that it may be useful to think of these processes as different facets of the same cell death continuum rather than completely separate processes.
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              Autophagy and cancer

              Basal autophagy plays a critical role in maintaining cellular homeostasis and genomic integrity by degrading aged or malfunctioning organelles and damaged or misfolded proteins. However, autophagy also plays a complicated role in tumorigenesis and treatment responsiveness. It can be tumor-suppressing during the early stages of tumorigenesis (i.e., it is an anti-tumor mechanism), as reduced autophagy is found in tumor cells and may be associated with malignant transformation. In this case, induction of autophagy would seem to be beneficial for cancer prevention. In established tumors, however, autophagy can be tumor-promoting (i.e., it is a pro-tumor mechanism), and cancer cells can use enhanced autophagy to survive under metabolic and therapeutic stress. The pharmacological and/or genetic inhibition of autophagy was recently shown to sensitize cancer cells to the lethal effects of various cancer therapies, including chemotherapy, radiotherapy and targeted therapies, suggesting that suppression of the autophagic pathway may represent a valuable sensitizing strategy for cancer treatments. In contrast, excessive stimulation of autophagy may also provide a therapeutic strategy for treating resistant cancer cells having high apoptotic thresholds. In order for us to develop successful autophagy-modulating strategies against cancer, we need to better understand how the roles of autophagy differ depending on the tumor stage, cell type and/or genetic factors, and we need to determine how specific pathways of autophagy are activated or inhibited by the various anti-cancer therapies.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                3 July 2014
                : 9
                : 7
                : e101526
                Affiliations
                [1 ]School of Life Sciences and Key Laboratory of Bio-resources and Eco-environment, Ministry of Education, Sichuan University, Chengdu, China
                [2 ]Central Laboratory of Clinical Medicine, Sichuan Academy of Medical Science & Sichuan Provincial People’s Hospital, Chengdu, China
                [3 ]Institute of Organ Transplantation, Sichuan Academy of Medical Science & Sichuan Provincial People’s Hospital, Chengdu, China
                [4 ]Department of Pharmacy, Sichuan Academy of Medical Science & Sichuan Provincial People’s Hospital, Chengdu, China
                [5 ]Center for Perinatal Research, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
                H. Lee Moffitt Cancer Center & Research Institute, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Performed the experiments: CL JC BL ZS HW. Analyzed the data: CL JC KZ BZ WQ. Contributed reagents/materials/analysis tools: CL JC KZ. Wrote the paper: CL JC JB YW. Designed the research: CL JB YW.

                Article
                PONE-D-14-02230
                10.1371/journal.pone.0101526
                4081584
                24992302
                b38c8076-3936-4459-b28b-c2f38786063d
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 15 January 2014
                : 8 June 2014
                Page count
                Pages: 12
                Funding
                This work was supported in part by the National Natural Science Foundation of China (No. 81373311, No. 31300674, No. 30970643, No. 81173093 and No. J1103518), the Special Program for Youth Science and the Technology Innovative Research Group of Sichuan Province, China (No. 2011JTD0026). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Chemical Biology
                Physical Sciences
                Chemistry

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                Uncategorized

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