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      Sinensetin Induces Autophagic Cell Death through p53-Related AMPK/mTOR Signaling in Hepatocellular Carcinoma HepG2 Cells

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          Abstract

          Sinensetin (SIN) has been reported to exhibit anti-inflammatory and anti-cancer activity. However, the cellular and molecular mechanism by which SIN promotes hepatocellular carcinoma (HCC) cell death remains unclear. In the present study, we investigated the induction of cell death by SIN and its underlying mechanism in HepG2 cells, an HCC cell line. We found that SIN significantly induced cell death in HepG2 cells, whereas the proliferation rate of Thle2, human liver epithelial cells, was unaffected by SIN. SIN-treated HepG2 cells were not affected by apoptotic cell death; instead, autophagic cell death was induced through the p53-mediated AMPK/mTOR signaling pathway. Inhibition of p53 degradation led to both autophagy and apoptosis in HepG2 cells. p53 translocation led to SIN-induced autophagy, whereas p53 translocation inhibited SIN-induced apoptosis. However, SIN showed apoptosis in the p53-mutant Hep3B cell line. Molecular docking simulation of the p53 core domain showed effective binding with SIN, which was found significant compared with the known p53 activator, RITA. Collectively, these data suggest that SIN may be a potential anti-cancer agent targeting autophagic cell death in human liver cancer.

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          Most cited references36

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          Regulation of autophagy by cytoplasmic p53.

          Multiple cellular stressors, including activation of the tumour suppressor p53, can stimulate autophagy. Here we show that deletion, depletion or inhibition of p53 can induce autophagy in human, mouse and nematode cells subjected to knockout, knockdown or pharmacological inhibition of p53. Enhanced autophagy improved the survival of p53-deficient cancer cells under conditions of hypoxia and nutrient depletion, allowing them to maintain high ATP levels. Inhibition of p53 led to autophagy in enucleated cells, and cytoplasmic, not nuclear, p53 was able to repress the enhanced autophagy of p53(-/-) cells. Many different inducers of autophagy (for example, starvation, rapamycin and toxins affecting the endoplasmic reticulum) stimulated proteasome-mediated degradation of p53 through a pathway relying on the E3 ubiquitin ligase HDM2. Inhibition of p53 degradation prevented the activation of autophagy in several cell lines, in response to several distinct stimuli. These results provide evidence of a key signalling pathway that links autophagy to the cancer-associated dysregulation of p53.
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            Revisiting the hallmarks of cancer.

            The hallmarks of cancer described by Hanahan and Weinberg have proved seminal in our understanding of cancer's common traits and in rational drug design. Not free of critique and with understanding of different aspects of tumorigenesis coming into clearer focus in the recent years, we attempt to draw a more organized and updated picture of the cancer hallmarks. We define seven hallmarks of cancer: selective growth and proliferative advantage, altered stress response favoring overall survival, vascularization, invasion and metastasis, metabolic rewiring, an abetting microenvironment, and immune modulation, while highlighting some considerations for the future of the field.
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              Morphologic and biochemical hallmarks of apoptosis.

              Apoptosis is characterised by a series of typical morphological features, such as shrinkage of the cell, fragmentation into membrane-bound apoptotic bodies and rapid phagocytosis by neighbouring cells. This paper reviews the current knowledge on the molecular mechanisms of apoptosis as they relate to the morphologic hallmarks and their implications for the detection of apoptosis in cardiac tissue. Activation of cysteine proteases called caspases plays a major role in the execution of apoptosis. These proteases selectively cleave vital cellular substrates, which results in apoptotic morphology and internucleosomal fragmentation of DNA by selectively activated DNases. In response to several pro-apoptotic signals, mitochondria release caspase activating factors, that initiate an escalating caspase cascade and commit the cell to die. Members of the Bcl-2 oncoprotein family control mitochondrial events and are able to prevent, or induce, both apoptotic and non-apoptotic types of cell death. This suggests that different types of cell death share common mechanisms in the early phases, whereas activation of caspases determines the phenotype of cell death. Detection of apoptotic cells in tissue samples currently relies on the TUNEL assay. TUNEL-positive cardiomyocytes show morphological features of apoptosis and the typical ladder pattern in DNA electrophoresis. Thus, provided that the staining protocol is carefully standardised, this quantitative methodology provides reproducible results of the occurrence of cardiomyocyte apoptosis in cardiac samples. Recently, potentially more specific assays based on analysis of DNA fragmentation or demonstration of caspase activation have been developed. Applicability of these assays to demonstrate cardiomyocyte apoptosis should be tested.
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                Author and article information

                Journal
                Nutrients
                Nutrients
                nutrients
                Nutrients
                MDPI
                2072-6643
                15 August 2020
                August 2020
                : 12
                : 8
                : 2462
                Affiliations
                [1 ]Research Institute of Life science and College of Veterinary Medicine, Gyeongsang National University, 501 Jinju-daero, Jinju 52828, Korea; ksm4234@ 123456naver.com (S.M.K.); sangdis2@ 123456naver.com (S.E.H.); preethivetrivel05@ 123456gmail.com (P.V.); shark159753@ 123456naver.com (H.H.K.)
                [2 ]Biological Resources Research Group, Bioenvironmental Science & Toxicology Division, Gyeongnam Branch Institute, Korea Institute of Toxicology (KIT), 17 Jeigok-gil, Jinju 52834, Korea; hojeong.lee@ 123456kitox.re.kr
                [3 ]Division of Life Sciences, Division of Applied Life Science (BK21 Plus), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Korea; shailima.rampogu@ 123456gmail.com (S.R.); kwlee@ 123456gnu.ac.kr (K.W.L.)
                [4 ]College of Pharmacy, Yonsei University, Incheon 21983, Korea; gowdavenu27@ 123456gmail.com
                Author notes
                [* ]Correspondence: gonskim@ 123456gnu.ac.kr ; Tel.: +82-55-772-2346
                Author information
                https://orcid.org/0000-0001-9646-195X
                https://orcid.org/0000-0002-0844-1009
                Article
                nutrients-12-02462
                10.3390/nu12082462
                7468969
                32824273
                a410ab2b-a5cd-443e-a9c5-6e041b4e8448
                © 2020 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 ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 24 April 2020
                : 12 August 2020
                Categories
                Article

                Nutrition & Dietetics
                sinensetin,autophagy,p53,ampk,hepatocellular carcinoma
                Nutrition & Dietetics
                sinensetin, autophagy, p53, ampk, hepatocellular carcinoma

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