Apoptosis: A Review of Programmed Cell Death

doi:10.1080/01926230701320337

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Apoptosis: A Review of Programmed Cell Death

Journal Article•DOI•

Apoptosis: A Review of Programmed Cell Death

Susan A. Elmore¹•Institutions (1)

Research Triangle Park¹

01 Jun 2007-Toxicologic Pathology (SAGE Publications)-Vol. 35, Iss: 4, pp 495-516

TL;DR: The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, the role of apoptoses in health and disease, detection methods, as well as a discussion of potential alternative forms of apoptotic proteins.

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Abstract: The process of programmed cell death, or apoptosis, is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Apoptosis is considered a vital component of various processes including normal cell turnover, proper development and functioning of the immune system, hormone-dependent atrophy, embryonic development and chemical-induced cell death. Inappropriate apoptosis (either too little or too much) is a factor in many human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer. The ability to modulate the life or death of a cell is recognized for its immense therapeutic potential. Therefore, research continues to focus on the elucidation and analysis of the cell cycle machinery and signaling pathways that control cell cycle arrest and apoptosis. To that end, the field of apoptosis research has been moving forward at an alarmingly rapid rate. Although many of the key apoptotic proteins have been identified, the molecular mechanisms of action or inaction of these proteins remain to be elucidated. The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, the role of apoptosis in health and disease, detection methods, as well as a discussion of potential alternative forms of apoptosis.

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Journal Article•DOI•

Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal.

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Antonio Ayala¹, Mario F. Muñoz¹, Sandro Argüelles¹•Institutions (1)

University of Seville¹

08 May 2014-Oxidative Medicine and Cellular Longevity

TL;DR: This review focuses on biochemical concepts of lipidPeroxidation, production, metabolism, and signaling mechanisms of two main omega-6 fatty acids lipid peroxidation products: malondialdehyde (MDA) and, in particular, 4-hydroxy-2-nonenal (4-HNE), summarizing not only its physiological and protective function as signaling molecule stimulating gene expression and cell survival, but also its cytotoxic role inhibiting geneexpression and promoting cell death.

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Abstract: Lipid peroxidation can be described generally as a process under which oxidants such as free radicals attack lipids containing carbon-carbon double bond(s), especially polyunsaturated fatty acids (PUFAs). Over the last four decades, an extensive body of literature regarding lipid peroxidation has shown its important role in cell biology and human health. Since the early 1970s, the total published research articles on the topic of lipid peroxidation was 98 (1970–1974) and has been increasing at almost 135-fold, by up to 13165 in last 4 years (2010–2013). New discoveries about the involvement in cellular physiology and pathology, as well as the control of lipid peroxidation, continue to emerge every day. Given the enormity of this field, this review focuses on biochemical concepts of lipid peroxidation, production, metabolism, and signaling mechanisms of two main omega-6 fatty acids lipid peroxidation products: malondialdehyde (MDA) and, in particular, 4-hydroxy-2-nonenal (4-HNE), summarizing not only its physiological and protective function as signaling molecule stimulating gene expression and cell survival, but also its cytotoxic role inhibiting gene expression and promoting cell death. Finally, overviews of in vivo mammalian model systems used to study the lipid peroxidation process, and common pathological processes linked to MDA and 4-HNE are shown.

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3,647 citations

Cites background from "Apoptosis: A Review of Programmed C..."

...The execution pathway results in characteristic cytomorphological features including cell shrinkage, chromatin condensation, formation of cytoplasmic blebs and apoptotic bodies, and finally phagocytosis of the apoptotic bodies by adjacent parenchymal cells, neoplastic cells or macrophages [352, 353]....
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...This pathway is triggered by the binding of death ligands of the tumor necrosis factor (TNF) family to their appropriate death receptors (DRs) on the cell surface; bestcharacterized ligands and corresponding death receptors include FasL/FasR and TNF-𝛼/TNFR1 [351, 352]....
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...This pathway is triggered by the binding of death ligands of the tumor necrosis factor (TNF) family to their appropriate death receptors (DRs) on the cell surface; bestcharacterized ligands and corresponding death receptors include FasL/FasR and TNF-α/TNFR1 [351, 352]....
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...This allows redistribution of cytochrome c from the mitochondrial intermembrane space into the cytoplasm, where it causes activation of caspase proteases and, subsequently, cell death [352, 353]....
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...Each pathway activates its own initiator caspase (8, 9) which in turn will activate the executioner caspase-3 [352]....
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Journal Article•DOI•

NF-κB, inflammation, immunity and cancer: coming of age

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Koji Taniguchi¹, Michael Karin²•Institutions (2)

Keio University¹, University of California, San Diego²

22 Jan 2018-Nature Reviews Immunology

TL;DR: How the initial discovery of a role for NF-κB in linking inflammation and cancer led to an improved understanding of tumour-elicited inflammation and its effects on anticancer immunity is discussed.

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Abstract: Fourteen years have passed since nuclear factor-κB (NF-κB) was first shown to serve as a molecular lynchpin that links persistent infections and chronic inflammation to increased cancer risk. The young field of inflammation and cancer has now come of age, and inflammation has been recognized by the broad cancer research community as a hallmark and cause of cancer. Here, we discuss how the initial discovery of a role for NF-κB in linking inflammation and cancer led to an improved understanding of tumour-elicited inflammation and its effects on anticancer immunity.

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1,545 citations

Journal Article•DOI•

JNK signaling in apoptosis.

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Danny N. Dhanasekaran¹, E P Reddy¹•Institutions (1)

Temple University¹

20 Oct 2008-Oncogene

TL;DR: This review analyses the present understanding of the role of JNK in apoptotic signaling and the various mechanisms by which JNK promotes apoptosis.

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Abstract: Jun N-terminal kinases or JNKs play a critical role in death receptor-initiated extrinsic as well as mitochondrial intrinsic apoptotic pathways. JNKs activate apoptotic signaling by the upregulation of pro-apoptotic genes through the transactivation of specific transcription factors or by directly modulating the activities of mitochondrial pro- and antiapoptotic proteins through distinct phosphorylation events. This review analyses our present understanding of the role of JNK in apoptotic signaling and the various mechanisms by which JNK promotes apoptosis.

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1,284 citations

Cites background from "Apoptosis: A Review of Programmed C..."

...Signaling pathways that initiate apoptosis have been broadly classified into (1) extrinsic pathways initiated by death receptors such as those of tumor necrosis factor (TNF)-a, TRAIL and FAS-L, and (2) intrinsic pathways initiated by mitochondrial events (Elmore, 2007)....
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Journal Article•DOI•

Combination therapy in combating cancer.

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Reza Bayat Mokhtari¹, Reza Bayat Mokhtari², Tina S. Homayouni, Narges Baluch³, Evgeniya Morgatskaya, Sushil Kumar, Bikul Das², Herman Yeger¹ - Show less +4 more•Institutions (3)

University of Toronto¹, The Forsyth Institute², Queen's University³

31 Mar 2017-Oncotarget

TL;DR: An approach that combines repurposed pharmaceutical agents with other therapeutics has shown promising results in mitigating tumour burden, and this systematic review discusses important pathways commonly targeted in cancer therapy.

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Abstract: // Reza Bayat Mokhtari 1,2,4 , Tina S. Homayouni 1 , Narges Baluch 3 , Evgeniya Morgatskaya 1 , Sushil Kumar 1 , Bikul Das 4 and Herman Yeger 1,2 1 Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada 2 Department of Paediatric Laboratory Medicine, The Hospital for Sick Children and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada 3 Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Ontario, Canada 4 Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, Massachusetts, USA Correspondence to: Herman Yeger, email: // Reza Bayat Mokhtari, email: // Keywords : Nrf2-Keap1, HIF-1alpha, carbonic anhydrase 9 (CAIX), histone deacetylase inhibitor (HDACi), carbonic anhydrase inhibitor (CAI) Received : October 19, 2016 Accepted : February 27, 2017 Published : March 30, 2017 Abstract Combination therapy, a treatment modality that combines two or more therapeutic agents, is a cornerstone of cancer therapy. The amalgamation of anti-cancer drugs enhances efficacy compared to the mono-therapy approach because it targets key pathways in a characteristically synergistic or an additive manner. This approach potentially reduces drug resistance, while simultaneously providing therapeutic anti-cancer benefits, such as reducing tumour growth and metastatic potential, arresting mitotically active cells, reducing cancer stem cell populations, and inducing apoptosis. The 5-year survival rates for most metastatic cancers are still quite low, and the process of developing a new anti-cancer drug is costly and extremely time-consuming. Therefore, new strategies that target the survival pathways that provide efficient and effective results at an affordable cost are being considered. One such approach incorporates repurposing therapeutic agents initially used for the treatment of different diseases other than cancer. This approach is effective primarily when the FDA-approved agent targets similar pathways found in cancer. Because one of the drugs used in combination therapy is already FDA-approved, overall costs of combination therapy research are reduced. This increases cost efficiency of therapy, thereby benefiting the “medically underserved”. In addition, an approach that combines repurposed pharmaceutical agents with other therapeutics has shown promising results in mitigating tumour burden. In this systematic review, we discuss important pathways commonly targeted in cancer therapy. Furthermore, we also review important repurposed or primary anti-cancer agents that have gained popularity in clinical trials and research since 2012.

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1,270 citations

Cites background from "Apoptosis: A Review of Programmed C..."

...These death receptors trigger intracellular signaling that results in the cleaving and activation of caspases such as caspase-3 and caspase-8, which ultimately lead to apoptosis [165, 166]....
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Journal Article•DOI•

Oxidative stress: the mitochondria-dependent and mitochondria-independent pathways of apoptosis

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Krishnendu Sinha¹, Joydeep Das¹, Pabitra Bikash Pal¹, Parames C. Sil¹•Institutions (1)

Bose Institute¹

30 Mar 2013-Archives of Toxicology

TL;DR: This review highlights the basic mechanisms of ROS production and their sites of formation; detail mechanism of both mitochondria-dependent and mitochondrial-independent pathways of apoptosis as well as their regulation by ROS and describes the involvement of oxidative stress under various environmental toxin- and drug-induced organ pathophysiology and diabetes-mediated apoptosis.

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Abstract: Oxidative stress basically defines a condition in which prooxidant-antioxidant balance in the cell is disturbed; cellular biomolecules undergo severe oxidative damage, ultimately compromising cells viability. In recent years, a number of studies have shown that oxidative stress could cause cellular apoptosis via both the mitochondria-dependent and mitochondria-independent pathways. Since these pathways are directly related to the survival or death of various cell types in normal as well as pathophysiological situations, a clear picture of these pathways for various active molecules in their biological functions would help designing novel therapeutic strategy. This review highlights the basic mechanisms of ROS production and their sites of formation; detail mechanism of both mitochondria-dependent and mitochondria-independent pathways of apoptosis as well as their regulation by ROS. Emphasis has been given on the redox-sensitive ASK1 signalosome and its downstream JNK pathway. This review also describes the involvement of oxidative stress under various environmental toxin- and drug-induced organ pathophysiology and diabetes-mediated apoptosis. We believe that this review would provide useful information about the most recent progress in understanding the mechanism of oxidative stress-mediated regulation of apoptotic pathways. It will also help to figure out the complex cross-talks between these pathways and their modulations by oxidative stress. The literature will also shed a light on the blind alleys of this field to be explored. Finally, readers would know about the ROS-regulated and apoptosis-mediated organ pathophysiology which might help to find their probable remedies in future.

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1,183 citations

Cites background from "Apoptosis: A Review of Programmed C..."

...It is to mention here that this mechanism is kept aside by cells as a late event and only occurs after the cell has committed to suicide (Elmore 2007)....
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...In T cells, Fas-induced apoptosis can be blocked by a protein called Toso, which inhibits the processing of caspase-8 (Hitoshi et al. 1998; Elmore 2007)....
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...mitochondrial membranes gets disturbed, resulting in the decrease in the mitochondrial transmembrane potential (DWm) and release of two main groups of proapoptotic proteins, which normally become sequestered at intermembrane space into the cytosol (Saelens et al. 2004; Elmore 2007)....
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...…integrity of mitochondrial membranes gets disturbed, resulting in the decrease in the mitochondrial transmembrane potential (DWm) and release of two main groups of proapoptotic proteins, which normally become sequestered at intermembrane space into the cytosol (Saelens et al. 2004; Elmore 2007)....
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...Among these, the Fas ligand/Fas receptor (FasL/FasR) and tumor necrosis factor a/tumor necrosis factor receptor 1 (TNFa/TNFR1) are the best-characterized models (Elmore 2007) that define the sequence of events in the extrinsic phase of apoptosis....
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References

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Journal Article•DOI•

Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics.

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J. F. R. Kerr, Andrew H. Wyllie, A. R. Currie

01 Aug 1972-British Journal of Cancer

TL;DR: Apoptosis seems to be involved in cell turnover in many healthy adult tissues and is responsible for focal elimination of cells during normal embryonic development, and participates in at least some types of therapeutically induced tumour regression.

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Abstract: The term apoptosis is proposed for a hitherto little recognized mechanism of controlled cell deletion, which appears to play a complementary but opposite role to mitosis in the regulation of animal cell populations. Its morphological features suggest that it is an active, inherently programmed phenomenon, and it has been shown that it can be initiated or inhibited by a variety of environmental stimuli, both physiological and pathological.The structural changes take place in two discrete stages. The first comprises nuclear and cytoplasmic condensation and breaking up of the cell into a number of membrane-bound, ultrastructurally well-preserved fragments. In the second stage these apoptotic bodies are shed from epithelial-lined surfaces or are taken up by other cells, where they undergo a series of changes resembling in vitro autolysis within phagosomes, and are rapidly degraded by lysosomal enzymes derived from the ingesting cells.Apoptosis seems to be involved in cell turnover in many healthy adult tissues and is responsible for focal elimination of cells during normal embryonic development. It occurs spontaneously in untreated malignant neoplasms, and participates in at least some types of therapeutically induced tumour regression. It is implicated in both physiological involution and atrophy of various tissues and organs. It can also be triggered by noxious agents, both in the embryo and adult animal.

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15,416 citations

"Apoptosis: A Review of Programmed C..." refers background in this paper

...Cancer is an example where the normal mechanisms of cell cycle regulation are dysfunctional, with either an overproliferation of cells and/or decreased removal of cells (King and Cidlowski, 1998)....
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Journal Article•DOI•

The biochemistry of apoptosis

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Michael O. Hengartner¹•Institutions (1)

Cold Spring Harbor Laboratory¹

12 Oct 2000-Nature

TL;DR: The basic components of the death machinery are reviewed, how they interact to regulate apoptosis in a coordinated manner is described, and the main pathways that are used to activate cell death are discussed.

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Abstract: Apoptosis - the regulated destruction of a cell - is a complicated process. The decision to die cannot be taken lightly, and the activity of many genes influence a cell's likelihood of activating its self-destruction programme. Once the decision is taken, proper execution of the apoptotic programme requires the coordinated activation and execution of multiple subprogrammes. Here I review the basic components of the death machinery, describe how they interact to regulate apoptosis in a coordinated manner, and discuss the main pathways that are used to activate cell death.

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7,255 citations

"Apoptosis: A Review of Programmed C..." refers background in this paper

...Biochemical Features: Apoptotic cells exhibit several biochemical modifications such as protein cleavage, protein cross-linking, DNA breakdown, and phagocytic recognition that together result in the distinctive structural pathology described previously (Hengartner, 2000)....
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Journal Article•DOI•

Death receptors: signaling and modulation

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Avi Ashkenazi¹, Vishva M. Dixit¹•Institutions (1)

Genentech¹

28 Aug 1998-Science

TL;DR: Apoptosis is a cell suicide mechanism that enables metazoans to control cell number in tissues and to eliminate individual cells that threaten the animal's survival.

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Abstract: Apoptosis is a cell suicide mechanism that enables metazoans to control cell number in tissues and to eliminate individual cells that threaten the animal's survival. Certain cells have unique sensors, termed death receptors, on their surface. Death receptors detect the presence of extracellular death signals and, in response, they rapidly ignite the cell's intrinsic apoptosis machinery.

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5,968 citations

"Apoptosis: A Review of Programmed C..." refers background in this paper

...Members of the TNF receptor family share similar cyteine-rich extracellular domains and have a cytoplasmic domain of about 80 amino acids called the “death domain” (Ashkenazi and Dixit, 1998)....
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Journal Article•DOI•

The green fluorescent protein

[...]

Roger Y. Tsien¹•Institutions (1)

University of California, San Diego¹

01 Jan 1998-Annual Review of Biochemistry

TL;DR: In just three years, the green fluorescent protein from the jellyfish Aequorea victoria has vaulted from obscurity to become one of the most widely studied and exploited proteins in biochemistry and cell biology.

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Abstract: In just three years, the green fluorescent protein (GFP) from the jellyfish Aequorea victoria has vaulted from obscurity to become one of the most widely studied and exploited proteins in biochemistry and cell biology. Its amazing ability to generate a highly visible, efficiently emitting internal fluorophore is both intrinsically fascinating and tremendously valuable. High-resolution crystal structures of GFP offer unprecedented opportunities to understand and manipulate the relation between protein structure and spectroscopic function. GFP has become well established as a marker of gene expression and protein targeting in intact cells and organisms. Mutagenesis and engineering of GFP into chimeric proteins are opening new vistas in physiological indicators, biosensors, and photochemical memories.

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5,954 citations

"Apoptosis: A Review of Programmed C..." refers background in this paper

...…control should be used to ensure that the staining conditions used are able to detect any available cytochrome c. Apoptotic or anti-apoptotic regulator proteins such as Bax, Bid, and Bcl-2 can also be detected using fluorescence and confocal microscopy (Tsien, 1998; Zhang et al., 2002)....
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Journal Article•DOI•

The phosphatidylinositol 3-Kinase AKT pathway in human cancer.

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Igor Vivanco¹, Charles L. Sawyers¹•Institutions (1)

University of California, Los Angeles¹

01 Jul 2002-Nature Reviews Cancer

TL;DR: Small-molecule therapeutics that block PI3K signalling might deal a severe blow to cancer cells by blocking many aspects of the tumour-cell phenotype.

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Abstract: One signal that is overactivated in a wide range of tumour types is the production of a phospholipid, phosphatidylinositol (3,4,5) trisphosphate, by phosphatidylinositol 3-kinase (PI3K) This lipid and the protein kinase that is activated by it — AKT — trigger a cascade of responses, from cell growth and proliferation to survival and motility, that drive tumour progression Small-molecule therapeutics that block PI3K signalling might deal a severe blow to cancer cells by blocking many aspects of the tumour-cell phenotype

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5,654 citations

"Apoptosis: A Review of Programmed C..." refers background in this paper

...In addition to regulation of apoptosis, this pathway regulates other cellular processes, such as proliferation, growth, and cytoskeletal rearrangement (Vivanco and Sawyers, 2002)....
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