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      Endoplasmic reticulum stress, cell death and tumor: Association between endoplasmic reticulum stress and the apoptosis pathway in tumors

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          Abstract

          External and internal stimuli are often involved in the pathogenesis of tumors, and the deterioration of endoplasmic reticulum (ER) function within cells is also an important etiological factor of tumorigenesis resulting in the impairment of the endoplasmic reticulum, which is termed ER stress. The ER is an organelle that serves a crucial role in the process of protein synthesis and maturation, and also acts as a reservoir of calcium to maintain intracellular Ca 2+ homeostasis. ER stress has been revealed to serve a critical role in tumorigenesis. In the present review, the association between ER stress-related pathways and tumor cell apoptosis is examined. Primarily, the role of ER stress in tumor cell apoptosis is discussed, and it is stipulated that ER stress, induced by drugs both directly and indirectly, promotes tumor cell apoptosis.

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          Most cited references94

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          Ferroptosis: an iron-dependent form of nonapoptotic cell death.

          Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.
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            The unfolded protein response: from stress pathway to homeostatic regulation.

            The vast majority of proteins that a cell secretes or displays on its surface first enter the endoplasmic reticulum (ER), where they fold and assemble. Only properly assembled proteins advance from the ER to the cell surface. To ascertain fidelity in protein folding, cells regulate the protein-folding capacity in the ER according to need. The ER responds to the burden of unfolded proteins in its lumen (ER stress) by activating intracellular signal transduction pathways, collectively termed the unfolded protein response (UPR). Together, at least three mechanistically distinct branches of the UPR regulate the expression of numerous genes that maintain homeostasis in the ER or induce apoptosis if ER stress remains unmitigated. Recent advances shed light on mechanistic complexities and on the role of the UPR in numerous diseases.
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              Targeting Ferroptosis to Iron Out Cancer

              One of the key challenges in cancer research is how to effectively kill cancer cells while leaving the healthy cells intact. Cancer cells often have defects in cell death executioner mechanisms, which is one of the main reasons for therapy resistance. To enable growth, cancer cells exhibit an increased iron demand compared with normal, non-cancer cells. This iron dependency can make cancer cells more vulnerable to iron-catalyzed necrosis, referred to as ferroptosis. The identification of FDA-approved drugs as ferroptosis inducers creates high expectations for the potential of ferroptosis to be a new promising way to kill therapy-resistant cancers.
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                Author and article information

                Journal
                Oncol Rep
                Oncol Rep
                Oncology Reports
                D.A. Spandidos
                1021-335X
                1791-2431
                March 2021
                12 January 2021
                12 January 2021
                : 45
                : 3
                : 801-808
                Affiliations
                [1 ]School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
                [2 ]Qingdao Municipal Hospital, Qingdao (Group), Qingdao, Shandong 266071, P.R. China
                [3 ]Qingdao Mental Health Center, Qingdao, Shandong 266071, P.R. China
                Author notes
                Correspondence to: Dr Xuehong Chen, School of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao, Shandong 266071, P.R. China, E-mail: chen-xuehong@ 123456163.com
                [*]

                Contributed equally

                Article
                or-45-03-0801
                10.3892/or.2021.7933
                7859917
                33469681
                234882ea-4315-41af-94be-d309bd477c06
                Copyright: © Fu et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 26 June 2020
                : 06 October 2020
                Funding
                Funded by: Shandong Key Research and Development Program Project
                Award ID: 2018GSF118124
                The present study was supported by the Shandong Key Research and Development Program Project (grant no. 2018GSF118124).
                Categories
                Review

                er stress,apoptosis,upr,tumor,oxidative stress,autophagy,immunogenic cell death,ferroptosis

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