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      Ethanol-Mediated Stress Promotes Autophagic Survival and Aggressiveness of Colon Cancer Cells via Activation of Nrf2/HO-1 Pathway


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          Epidemiological studies suggest that chronic alcohol consumption is a lifestyle risk factor strongly associated with colorectal cancer development and progression. The aim of the present study was to examine the effect of ethanol (EtOH) on survival and progression of three different colon cancer cell lines (HCT116, HT29, and Caco-2). Our data showed that EtOH induces oxidative and endoplasmic reticulum (ER) stress, as demonstrated by reactive oxygen species (ROS) and ER stress markers Grp78, ATF6, PERK and, CHOP increase. Moreover, EtOH triggers an autophagic response which is accompanied by the upregulation of beclin, LC3-II, ATG7, and p62 proteins. The addition of the antioxidant N-acetylcysteine significantly prevents autophagy, suggesting that autophagy is triggered by oxidative stress as a prosurvival response. EtOH treatment also upregulates the antioxidant enzymes SOD, catalase, and heme oxygenase (HO-1) and promotes the nuclear translocation of both Nrf2 and HO-1. Interestingly, EtOH also upregulates the levels of matrix metalloproteases (MMP2 and MMP9) and VEGF. Nrf2 silencing or preventing HO-1 nuclear translocation by the protease inhibitor E64d abrogates the EtOH-induced increase in the antioxidant enzyme levels as well as the migration markers. Taken together, our results suggest that EtOH mediates both the activation of Nrf2 and HO-1 to sustain colon cancer cell survival, thus leading to the acquisition of a more aggressive phenotype.

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          Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors.

          In this article, the incidence, mortality, and survival rates for colorectal cancer are reviewed, with attention paid to regional variations and changes over time. A concise overview of known risk factors associated with colorectal cancer is provided, including familial and hereditary factors, as well as environmental lifestyle-related risk factors such as physical inactivity, obesity, smoking, and alcohol consumption.
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            The endoplasmic reticulum (ER) is a specialized organelle for the folding and trafficking of proteins, which is highly sensitive to changes in intracellular homeostasis and extracellular stimuli. Alterations in the protein-folding environment cause accumulation of misfolded proteins in the ER that profoundly affect a variety of cellular signaling processes, including reduction-oxidation (redox) homeostasis, energy production, inflammation, differentiation, and apoptosis. The unfolded protein response (UPR) is a collection of adaptive signaling pathways that evolved to resolve protein misfolding and restore an efficient protein-folding environment. Production of reactive oxygen species (ROS) has been linked to ER stress and the UPR. ROS play a critical role in many cellular processes and can be produced in the cytosol and several organelles, including the ER and mitochondria. Studies suggest that altered redox homeostasis in the ER is sufficient to cause ER stress, which could, in turn, induce the production of ROS in the ER and mitochondria. Although ER stress and oxidative stress coexist in many pathologic states, whether and how these stresses interact is unknown. It is also unclear how changes in the protein-folding environment in the ER cause oxidative stress. In addition, how ROS production and protein misfolding commit the cell to an apoptotic death and contribute to various degenerative diseases is unknown. A greater fundamental understanding of the mechanisms that preserve protein folding homeostasis and redox status will provide new information toward the development of novel therapeutics for many human diseases.
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              Crosstalk of ER stress-mediated autophagy and ER-phagy: Involvement of UPR and the core autophagy machinery.

              Endoplasmic reticulum (ER) stress, a common cellular stress response, is closely related to the activation of autophagy that is an important and evolutionarily conserved mechanism for maintaining cellular homeostasis. Autophagy induced by ER stress mainly includes the ER stress-mediated autophagy and ER-phagy. The ER stress-mediated autophagy is characterized by the generation of autophagosomes that include worn-out proteins, protein aggregates, and damaged organelles. While the autophagosomes of ER-phagy selectively include ER membranes, and the double membranes also derive, at least in part, from the ER. The signaling pathways of IRE1α, PERK, ATF6, and Ca2+ are necessary for the activation of ER stress-mediated autophagy, while the receptor-mediated selective ER-phagy degrades the ER is Atg40/FAM134B. The ER stress-mediated autophagy and ER-phagy not only have differences, but also have connections. The activation of ER-phagy requires the core autophagy machinery, and the ER-phagy may be a branch of ER stress-mediated autophagy that selectively targets the ER. However, the determined factors that control the changeover switch between ER stress-mediated autophagy and ER-phagy are largely obscure, which may be associated with the type of cells and the extent of stimulation. This review summarized the crosstalk between ER stress-mediated autophagy and ER-phagy and their signaling networks. Additionally, we discussed the possible factors that influence the type of autophagy induced by ER stress.

                Author and article information

                Cancers (Basel)
                Cancers (Basel)
                10 April 2019
                April 2019
                : 11
                : 4
                : 505
                [1 ]Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Institute of Biochemistry, University of Palermo, 90127 Palermo, Italy; cesare.cernigliaro@ 123456unipa.it (C.C.); daniela.carlisi@ 123456unipa.it (D.C.); sonia.emanuele@ 123456unipa.it (S.E.)
                [2 ]Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), Laboratory of Biochemistry, University of Palermo, 90127 Palermo, Italy; antonella.danneo@ 123456unipa.it (A.D.); michela.giuliano@ 123456unipa.it (M.G.); giuseppe.calvaruso@ 123456unipa.it (G.C.)
                [3 ]Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Institute of Human Anatomy, University of Palermo, 90127 Palermo, Italy; antonella.marino@ 123456hotmail.it (A.M.G.); rosario.barone@ 123456unipa.it (R.B.); francapp@ 123456hotmail.com (F.C.); claudiettacam@ 123456hotmail.com (C.C.)
                [4 ]Euro-Mediterranean Institute of Science and Technology, 90100 Palermo, Italy
                [5 ]Department of Biomedical and Biotechnological Sciences, University of Catania, I-95123 Catania, Italy; lucia.longhitano@ 123456unict.it (L.L.); distalfio@ 123456gmail.com (A.D.)
                Author notes
                [* ]Correspondence: marianna.lauricella@ 123456unipa.it ; Tel.: +39-091-6552457

                These authors contributed equally to this work as first author.

                Author information
                © 2019 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/).

                : 11 February 2019
                : 07 April 2019

                colon cancer cells,ethanol,nrf2,ho-1,er stress,autophagy,mmps
                colon cancer cells, ethanol, nrf2, ho-1, er stress, autophagy, mmps


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