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      δ‐Tocotrienol induces apoptosis, involving endoplasmic reticulum stress and autophagy, and paraptosis in prostate cancer cells


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          Prostate cancer, after the phase of androgen dependence, may progress to the castration‐resistant prostate cancer (CRPC) stage, with resistance to standard therapies. Vitamin E‐derived tocotrienols (TTs) possess a significant antitumour activity. Here, we evaluated the anti‐cancer properties of δ‐TT in CRPC cells (PC3 and DU145) and the related mechanisms of action.

          Materials and methods

          MTT, Trypan blue and colony formation assays were used to assess cell viability/cell death/cytotoxicity. Western blot, immunofluorescence and MTT analyses were utilized to investigate apoptosis, ER stress and autophagy. Morphological changes were investigated by light and transmission electron microscopy.


          We demonstrated that δ‐TT exerts a cytotoxic/proapoptotic activity in CRPC cells. We found that in PC3 cells: (a) δ‐TT triggers both the endoplasmic reticulum (ER) stress and autophagy pathways; (b) autophagy induction is related to the ER stress, and this ER stress/autophagy axis is involved in the antitumour activity of δ‐TT; in autophagy‐defective DU145 cells, only the ER stress pathway is involved in the proapoptotic effects of δ‐TT; (c) in both CRPC cell lines, δ‐TT also induces an intense vacuolation prevented by the ER stress inhibitor salubrinal and the protein synthesis inhibitor cycloheximide, together with increased levels of phosphorylated JNK and p38, supporting the induction of paraptosis by δ‐TT.


          These data demonstrate that apoptosis, involving ER stress and autophagy (in autophagy positive PC3 cells), and paraptosis are involved in the anti‐cancer activity of δ‐TT in CRPC cells.

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          Most cited references51

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          An alternative, nonapoptotic form of programmed cell death.

          The term apoptosis often has been used interchangeably with the term programmed cell death. Here we describe a form of programmed cell death that is distinct from apoptosis by the criteria of morphology, biochemistry, and response to apoptosis inhibitors. Morphologically, this alternative form of programmed cell death appears during development and in some cases of neurodegeneration. Despite its lack of response to caspase inhibitors and Bcl-x(L), we show that this form of cell death is driven by an alternative caspase-9 activity that is Apaf-1-independent. Characterization of this alternative form of programmed cell death should lead to new insight into cell death programs and their roles in development and degeneration.
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            Endoplasmic Reticulum Stress: Its Role in Disease and Novel Prospects for Therapy

            The endoplasmic reticulum (ER) is a multifunctional organelle required for lipid biosynthesis, calcium storage, and protein folding and processing. A number of physiological and pathological conditions, as well as a variety of pharmacological agents, are able to disturb proper ER function and thereby cause ER stress, which severely impairs protein folding and therefore poses the risk of proteotoxicity. Specific triggers for ER stress include, for example, particular intracellular alterations (e.g., calcium or redox imbalances), certain microenvironmental conditions (e.g., hypoglycemia, hypoxia, and acidosis), high-fat and high-sugar diet, a variety of natural compounds (e.g., thapsigargin, tunicamycin, and geldanamycin), and several prescription drugs (e.g., bortezomib/Velcade, celecoxib/Celebrex, and nelfinavir/Viracept). The cell reacts to ER stress by initiating a defensive process, called the unfolded protein response (UPR), which is comprised of cellular mechanisms aimed at adaptation and safeguarding cellular survival or, in cases of excessively severe stress, at initiation of apoptosis and elimination of the faulty cell. In recent years, this dichotomic stress response system has been linked to several human diseases, and efforts are underway to develop approaches to exploit ER stress mechanisms for therapy. For example, obesity and type 2 diabetes have been linked to ER stress-induced failure of insulin-producing pancreatic beta cells, and current research efforts are aimed at developing drugs that ameliorate cellular stress and thereby protect beta cell function. Other studies seek to pharmacologically aggravate chronic ER stress in cancer cells in order to enhance apoptosis and achieve tumor cell death. In the following, these principles will be presented and discussed.
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              Is Open Access

              Cytoplasmic vacuolization in cell death and survival

              Cytoplasmic vacuolization (also called cytoplasmic vacuolation) is a well-known morphological phenomenon observed in mammalian cells after exposure to bacterial or viral pathogens as well as to various natural and artificial low-molecular-weight compounds. Vacuolization often accompanies cell death; however, its role in cell death processes remains unclear. This can be attributed to studying vacuolization at the level of morphology for many years. At the same time, new data on the molecular mechanisms of the vacuole formation and structure have become available. In addition, numerous examples of the association between vacuolization and previously unknown cell death types have been reported. Here, we review these data to make a deeper insight into the role of cytoplasmic vacuolization in cell death and survival.

                Author and article information

                Cell Prolif
                Cell Prolif
                Cell Proliferation
                John Wiley and Sons Inc. (Hoboken )
                04 February 2019
                May 2019
                : 52
                : 3 ( doiID: 10.1111/cpr.2019.52.issue-3 )
                : e12576
                [ 1 ] Department of Pharmacological and Biomolecular Sciences Università degli Studi di Milano Milano Italy
                [ 2 ] Department of Environmental Science and Policy Università degli Studi di Milano Milano Italy
                [ 3 ] Department of Biomedical Sciences for Health Università degli Studi di Milano Milano Italy
                Author notes
                [*] [* ] Correspondence

                Patrizia Limonta, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy.

                Email: patrizia.limonta@ 123456unimi.it

                © 2019 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                : 12 September 2018
                : 30 November 2018
                : 28 December 2018
                Page count
                Figures: 8, Tables: 0, Pages: 15, Words: 7469
                Funded by: MIUR Progetto di Eccellenza (Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano) , open-funder-registry 10.13039/501100003407;
                Funded by: PRIN 2015
                Award ID: 2015B7M39T_004
                Funded by: Fondazione Banca del Monte di Lombardia, Pavia
                Original Article
                Original Articles
                Custom metadata
                May 2019
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.2 mode:remove_FC converted:05.12.2019

                Cell biology
                apoptosis,autophagy,er stress,paraptosis,prostate cancer,δ‐tocotrienol
                Cell biology
                apoptosis, autophagy, er stress, paraptosis, prostate cancer, δ‐tocotrienol


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