Recent Findings of the Types of Programmed Cell Death

Summary Cell death plays an important role in maintaining the homeostasis of multicellular organisms. It can occur in a controlled manner by apoptosis or autophagy. Cell death which occurs regardless of regulatory factors include necrosis, mitotic catastrophe or oncosis. Apoptosis and necrosis are cellular process that leads to cell death. However their mechanisms are different, although factors triggering them can be similar. Necrosis and apoptosis have many different characteristics in terms of biochemistry and morphology. There are two main pathways of apoptosis induction signal: receptor - dependent and mitochondrial. The outsider apoptotic pathway is induced by external factors stimulating membrane receptors having an intracellular domain called death domain. Mitochondrial apoptotic pathway is activated by increased concentration of reactive oxygen species (ROS), DNA damage, disorders electrolyte transport and an increase in the concentration of the calcium ions in the cytoplasm. In response to stress-factors, mitochondrial channels are opened, so that is released into the cytoplasm cytochrome C. This work is aimed at an overall description of exchanged processes.

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Current and Emerging Biomarkers of Cell Death in Human Disease

BioMed Research International ◽

10.1155/2014/690103 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 7

Author(s):

Kongning Li ◽

Deng Wu ◽

Xi Chen ◽

Ting Zhang ◽

Lu Zhang ◽

...

Keyword(s):

Cell Death ◽

Molecular Mechanisms ◽

Research Area ◽

Human Diseases ◽

Mitotic Catastrophe ◽

Regulated Necrosis ◽

Early Diagnose ◽

Multicellular Organisms ◽

The Relationship ◽

Made In

Cell death is a critical biological process, serving many important functions within multicellular organisms. Aberrations in cell death can contribute to the pathology of human diseases. Significant progress made in the research area enormously speeds up our understanding of the biochemical and molecular mechanisms of cell death. According to the distinct morphological and biochemical characteristics, cell death can be triggered by extrinsic or intrinsic apoptosis, regulated necrosis, autophagic cell death, and mitotic catastrophe. Nevertheless, the realization that all of these efforts seek to pursue an effective treatment and cure for the disease has spurred a significant interest in the development of promising biomarkers of cell death to early diagnose disease and accurately predict disease progression and outcome. In this review, we summarize recent knowledge about cell death, survey current and emerging biomarkers of cell death, and discuss the relationship with human diseases.

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Apoptosis, guardian of the genome: Review

World Journal of Biology Pharmacy and Health Sciences ◽

10.30574/wjbphs.2021.5.1.0003 ◽

2021 ◽

Vol 5 (1) ◽

pp. 037-054

Author(s):

Ahmad Mohammad Khalil

Keyword(s):

Cell Death ◽

Growth And Development ◽

Scientific Community ◽

Direct Result ◽

Life And Death ◽

Cellular Events ◽

Response To Stress ◽

Biochemical Mechanisms ◽

Number Of Publications ◽

Multicellular Organisms

Apoptosis has attracted great attention in the last two decades and the number of publications related to apoptosis has been growing exponentially. The revolution that has occurred in apoptosis research is a direct result of a better understanding of the genetic program and biochemical mechanisms of apoptosis. Apoptosis is not only a common normal event but also essential for the growth and development of organisms. In the adult, apoptosis is mostly abnormal, but in its absence or failure cancer cells obtain immortality by escaping this type of cell death. Apoptosis works synergistically in intrinsic and extrinsic pathways. The first pathway is initiated by the cell itself in response to stress. The second is initiated via death receptors stimulated by cells of the immune system. This review is an attempt to answer questions like: Why is cell death important to study? How cells undergo apoptosis? What controls the decision between life and death? Which cellular events could cause the control of apoptosis to be impaired? The literature cited below shows some sort of unity in the scientific community on the necessity of a sophisticated balance between “pro-survival” and “pro-death” forces to ensure the happiness of cells in multicellular organisms

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The Novel PARP Inhibitor, AZD2281, Targets Apoptotic Resistant ATM Mutant CLL Tumours for Cellular Killing.

Blood ◽

10.1182/blood.v108.11.2110.2110 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2110-2110

Author(s):

Victoria Weston ◽

Claire Baker ◽

Belinda Austen ◽

Malcolm Taylor ◽

Paul Moss ◽

...

Keyword(s):

Cell Death ◽

Parp Inhibitor ◽

Significant Proportion ◽

Tumour Cells ◽

Mitotic Catastrophe ◽

Parp Inhibition ◽

Wild Type ◽

Apoptotic Pathway ◽

Tissue Tumour ◽

Parp Activity

Abstract B-CLL is incurable and the development of resistance to standard chemotherapeutics remains an important problem. ATM mutations lead to chemo-resistance in a significant proportion of CLL patients and this is due to impairment in the activation of the DNA-damage induced ATM/p53 apoptotic pathway. Therefore, there is a requirement for novel treatments for ATM mutant CLL tumours, which induce cell death by mechanisms that are independent of this pathway. Breast cancer cells with homozygous BRCA1/2 mutations are deficient in the repair of DNA double strand break (DSB) by homologous recombination (HR). It has recently been shown that inhibition of PARP activity, which is required for repair of DNA single strand breaks (SSB), can lead to selective sensitisation of tumours harbouring BRCA1/2 mutations in replicating cells. The mechanism involves the continual progression of DNA SSBs into DSBs, which in the presence of defective HR, results in accumulation of DSBs and activation of cell death via mitotic catastrophe. ATM regulates the balance between the repair of DNA DSBs and the induction of the DNA DSB apoptotic pathway. Therefore, the phenotype of ATM mutant CLL cells includes a repair defect as well as an apoptotic defect. By analogy with the BRCA study, we investigated whether PARP inhibition can sensitise ATM mutant CLL tumours. We addressed the in vitro cytotoxicity of a similar PARP inhibitor (PARPi), AZD2281 produced by KuDOS, in 20 CLL tumours, including 10 ATM mutant and 10 ATM wild type. We analysed each of the CLL tumours in non-cycling and cycling states in culture. The aim was to mimic the CLL tumour populations in vivo, which are believed to consist of non-cycling peripheral blood tumour cells and cycling lymphoid tissue tumour cells. Given the mechanism of PARP activity, we predicted that its inhibition would preferentially be toxic in the cycling CLL population. In our experiments, CLL cycling was induced using a CD40L/IL4 support system and verified by incorporation of tritiated thymidine or BrdU. Consistent with our expectations, non-cycling CLL cells did not show significant cytotoxicity to increasing doses of AZD2281 (0.5–10μM). By comparison, in cycling CLLs there was increased sensitivity to AZD2281 at concentrations of 1.5μM or greater in ATM mutant compared to ATM wild type tumours. Furthermore, protein analysis revealed that treatment with AZD2281 did not induce the up regulation of p53 or the cleavage of caspases and that the killing in ATM mutant cells did not require induction of Atm/p53 dependent apoptosis. In non-cycling ATM mutant CLL cells, we also investigated whether pre-incubation with the AZD2281 could sensitize cells to DNA damaging chemotherapeutics. Interestingly, we found that 24 hours pre-treatment with AZD2281 rendered ATM mutant non-cycling cells sensitive to Fludarabine. We conclude that the PARP inhibitor AZD2281 is capable of targeting CLL cells with defective ATM function for cellular killing. Furthermore, our results indicate that inhibition of PARP is particularly important in the induction of cell death within proliferating ATM mutant CLL cells, which play a major role in tumour progression. Also, the addition of AZD2281 can sensitise non-cycling ATM mutant tumour cells to killing by Fludarabine. Our results suggest that this compound could be effective in the treatment of CLL patients with apoptotic resistant ATM mutant tumours.

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EspC, an Autotransporter Protein Secreted by EnteropathogenicEscherichia coli, Causes Apoptosis and Necrosis through Caspase and Calpain Activation, Including Direct Procaspase-3 Cleavage

mBio ◽

10.1128/mbio.00479-16 ◽

2016 ◽

Vol 7 (3) ◽

Cited By ~ 16

Author(s):

Antonio Serapio-Palacios ◽

Fernando Navarro-Garcia

Keyword(s):

Cell Death ◽

Epithelial Cells ◽

Intracellular Calcium ◽

Serine Protease ◽

Focal Adhesion ◽

Apoptotic Pathway ◽

Mitochondrial Apoptotic Pathway ◽

Calpain Activation ◽

Functional Relationships ◽

Apoptosis And Necrosis

ABSTRACTEnteropathogenicEscherichia coli(EPEC) has the ability to antagonize host apoptosis during infection through promotion and inhibition of effectors injected by the type III secretion system (T3SS), but the total number of these effectors and the overall functional relationships between these effectors during infection are poorly understood. EspC produced by EPEC cleaves fodrin, paxillin, and focal adhesion kinase (FAK), which are also cleaved by caspases and calpains during apoptosis. Here we show the role of EspC in cell death induced by EPEC. EspC is involved in EPEC-mediated cell death and induces both apoptosis and necrosis in epithelial cells. EspC induces apoptosis through the mitochondrial apoptotic pathway by provoking (i) a decrease in the expression levels of antiapoptotic protein Bcl-2, (ii) translocation of the proapoptotic protein Bax from cytosol to mitochondria, (iii) cytochromecrelease from mitochondria to the cytoplasm, (iv) loss of mitochondrial membrane potential, (v) caspase-9 activation, (vi) cleavage of procaspase-3 and (vii) an increase in caspase-3 activity, (viii) PARP proteolysis, and (ix) nuclear fragmentation and an increase in the sub-G1population. Interestingly, EspC-induced apoptosis was triggered through a dual mechanism involving both independent and dependent functions of its EspC serine protease motif, the direct cleavage of procaspase-3 being dependent on this motif. This is the first report showing a shortcut for induction of apoptosis by the catalytic activity of an EPEC protein. Furthermore, this atypical intrinsic apoptosis appeared to induce necrosis through the activation of calpain and through the increase of intracellular calcium induced by EspC. Our data indicate that EspC plays a relevant role in cell death induced by EPEC.IMPORTANCEEspC, an autotransporter protein with serine protease activity, has cytotoxic effects on epithelial cells during EPEC infection. EspC causes cytotoxicity by cleaving fodrin, a cytoskeletal actin-associated protein, and focal adhesion proteins (i.e., FAK); interestingly, these proteins are also cleaved during apoptosis and necrosis. Here we show that EspC is able to cause cell death, which is characterized by apoptosis: by dissecting the apoptotic pathway and considering that EspC is translocated by an injectisome, we found that EspC induces the mitochondrial apoptotic pathway. Remarkably, EspC activates this pathway by two distinct mechanisms—either by using or not using its serine protease motif. Thus, we show for the first time that this serine protease motif is able to cleave procaspase-3, thereby reaching the terminal stages of caspase cascade activation leading to apoptosis. Furthermore, this overlapped apoptosis appears to potentiate cell death through necrosis, where EspC induces calpain activation and increases intracellular calcium.

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Disturbances in the Mechanism of Apoptosis as One of the Causes of the Development of Cancer Diseases

Studia Ecologiae et Bioethicae ◽

10.21697/seb.2020.18.4.06 ◽

2020 ◽

Vol 18 (4) ◽

pp. 63-73

Author(s):

Paweł Rusin ◽

Karolina Jabłońska

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Death Receptor ◽

The Body ◽

Stress Factors ◽

Cancerous Cell ◽

Anticancer Treatment ◽

Apoptotic Pathways ◽

Apoptosis Regulation ◽

Multicellular Organisms

Apoptosis is a genetically programmed process that affects all multicellular organisms. This mechanism of programmed cell death is designed to protect the body against uncontrolled proliferation of cells with impaired functions. Apoptosis can occur through two major pathways. The extrinsic, initiated by signals from the death receptor, and the intrinsic one, resulting from a change in the permeability of the external mitochondrial membrane due to stress factors promoting the initiation of programmed cell death. Apoptosis may be influenced by many factors that may lead to suppressing the initiation of apoptotic pathways, and the damaged cell will develop, divide, and over time transform into a cancerous cell. As a result, cancer cells will be resistant to the applied chemo- and radiotherapy. The mechanisms responsible for apoptosis regulation are impaired, what eliminates the effects of therapies aimed at initiating this type of cell death. New types of molecular therapies provide an opportunity to increase the effectiveness of anticancer treatment, aiming at deficient proteins and suppressing or eliminating their antiapoptotic effects.

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Potential for Modulation of the Fas Apoptotic Pathway by Epidermal Growth Factor in Sarcomas

Sarcoma ◽

10.1155/2011/847409 ◽

2011 ◽

Vol 2011 ◽

pp. 1-15 ◽

Cited By ~ 1

Author(s):

David E. Joyner ◽

Kevin B. Jones ◽

Stephen L. Lessnick ◽

Joshua D. Schiffman ◽

R. Lor Randall

Keyword(s):

Cell Death ◽

Growth Factor ◽

Fas Ligand ◽

Death Domain ◽

Apoptotic Pathway ◽

Viable Cells ◽

Therapeutic Mechanism ◽

Epidermal Growth ◽

Fas Pathway

One important mechanism by which cancer cells parasitize their host is by escaping apoptosis. Thus, selectively facilitating apoptosis is a therapeutic mechanism by which oncotherapy may prove highly advantageous. One major apoptotic pathway is mediated by Fas ligand (FasL). The death-inducing signaling Ccmplex (DISC) and subsequent death-domain aggregations are created when FasL is bound by its receptor thereby enabling programmed cell death. Conceptually, if a better understanding of the Fas pathway can be garnered, an oncoselective prodeath therapeutic approach can be tailored. Herein, we propose that EGF and CTGF play essential roles in the regulation of the Fas apoptotic pathway in sarcomas. Tumor andin vitrodata suggest viable cells counter the prodeath signal induced by FasL by activating EGF, which in turn induces prosurvival CTGF. The prosurvival attributes of CTGF ultimately predominate over the death-inducing FasL. Cells destined for elimination inhibit this prosurvival response via a presently undefined pathway. This scenario represents a novel role for EGF and CTGF as regulators of the Fas pathway in sarcomas.

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Programmed cell death: genes involved in signaling, regulation, and execution in plants and animals

Botany ◽

10.1139/cjb-2014-0152 ◽

2015 ◽

Vol 93 (4) ◽

pp. 193-210 ◽

Cited By ~ 30

Author(s):

Gaolathe Rantong ◽

Arunika H.L.A.N. Gunawardena

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Morphological Characteristics ◽

Special Focus ◽

Apoptotic Pathway ◽

Signaling Regulation ◽

Whole Plant ◽

Cell Death Genes ◽

Death Genes ◽

Multicellular Organisms

Programmed cell death (PCD) is a suicide mechanism adopted by multicellular organisms that is essential for development and resistance to different forms of stress. In plants, PCD is involved from embryogenesis to death of the whole plant. PCD is genetically regulated and the molecular pathways involved in different forms of this process in animals are relatively more understood than in plants. At the morphological level, apoptosis, one of the forms of PCD in animals, and plant PCD have some similarities such as cell shrinkage, shrinkage of the nucleus, and DNA fragmentation. Because morphological characteristics are a product of the genetically encoded PCD mechanism, it is of interest to figure out how much of the apoptotic pathway is shared with plant PCD in terms of the genes involved. Evidence of some level of similarities has been gathered in the last decade, supporting conservation during signaling, regulation, and execution of apoptosis and plant PCD. A continued search into the genomes of plants has provided insights about homologues of apoptosis genes present in plants, and functional analysis provides evidence about which genes are carrying out similar roles during apoptosis and plant PCD. This review is aimed at updating on the progress of plant PCD mechanism research and highlighting some of the similarities and differences between plant and mammalian PCD mechanisms, with special focus on the commonalities.

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Apoptosis and development

Essays in Biochemistry ◽

10.1042/bse0390011 ◽

2003 ◽

Vol 39 ◽

pp. 11-24 ◽

Cited By ~ 6

Author(s):

Justin V McCarthy

Keyword(s):

Drosophila Melanogaster ◽

Mammalian Cells ◽

Cell Number ◽

Model Organisms ◽

Biological Processes ◽

Nematode Caenorhabditis Elegans ◽

Apoptotic Pathway ◽

Genetic Pathways ◽

Evolutionarily Conserved ◽

Multicellular Organisms

Apoptosis is an evolutionarily conserved process used by multicellular organisms to developmentally regulate cell number or to eliminate cells that are potentially detrimental to the organism. The large diversity of regulators of apoptosis in mammalian cells and their numerous interactions complicate the analysis of their individual functions, particularly in development. The remarkable conservation of apoptotic mechanisms across species has allowed the genetic pathways of apoptosis determined in lower species, such as the nematode Caenorhabditis elegans and the fruitfly Drosophila melanogaster, to act as models for understanding the biology of apoptosis in mammalian cells. Though many components of the apoptotic pathway are conserved between species, the use of additional model organisms has revealed several important differences and supports the use of model organisms in deciphering complex biological processes such as apoptosis.

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Activation of the intrinsic-apoptotic pathway in LNCaP prostate cancer cells by genistein- topotecan combination treatments

Functional Foods in Health and Disease ◽

10.31989/ffhd.v3i3.64 ◽

2013 ◽

Vol 3 (3) ◽

pp. 66 ◽

Cited By ~ 2

Author(s):

Vanessa Hörmann ◽

Sivanesan Dhandayuthapani ◽

James Kumi-Diaka ◽

Appu Rathinavelu

Keyword(s):

Prostate Cancer ◽

Cell Death ◽

Cancer Cells ◽

Apoptotic Cell ◽

Treatment Options ◽

Attractive Alternative ◽

Intrinsic Apoptotic Pathway ◽

Prostate Cancer Cells ◽

Apoptotic Pathway ◽

Combination Treatments

Background: Prostate cancer is the second most common cancer in American men. The development of alternative preventative and/or treatment options utilizing a combination of phytochemicals and chemotherapeutic drugs could be an attractive alternative compared to conventional carcinoma treatments. Genistein isoflavone is the primary dietary phytochemical found in soy and has demonstrated anti-tumor activities in LNCaP prostate cancer cells. Topotecan Hydrochloride (Hycamtin) is an FDA-approved chemotherapy for secondary treatment of lung, ovarian and cervical cancers. The purpose of this study was to detail the potential activation of the intrinsic apoptotic pathway in LNCaP prostate cancer cells through genistein-topotecan combination treatments. Methods: LNCaP cells were cultured in complete RPMI medium in a monolayer (70-80% confluency) at 37ºC and 5% CO2. Treatment consisted of single and combination groups of genistein and topotecan for 24 hours. The treated cells were assayed for i) growth inhibition through trypan blue exclusion assay and microphotography, ii) classification of cellular death through acridine/ ethidium bromide fluorescent staining, and iii) activation of the intrinsic apoptotic pathway through Jc-1: mitochondrial membrane potential assay, cytochrome c release and Bcl-2 protein expression.Results: The overall data indicated that genistein-topotecan combination was significantly more efficacious in reducing the prostate carcinoma’s viability compared to the single treatment options. In all treatment groups, cell death occurred primarily through the activation of the intrinsic apoptotic pathway.Conclusion: The combination of topotecan and genistein has the potential to lead to treatment options with equal therapeutic efficiency as traditional chemo- and radiation therapies, but lower cell cytotoxicity and fewer side effects in patients. Key words: topotecan; genistein; intrinsic apoptotic cell death

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Progress in understanding the role of lncRNA in programmed cell death

Cell Death Discovery ◽

10.1038/s41420-021-00407-1 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Na Jiang ◽

Xiaoyu Zhang ◽

Xuejun Gu ◽

Xiaozhuang Li ◽

Lei Shang

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Molecular Mechanisms ◽

Membrane Receptors ◽

Gene Expressions ◽

Apoptosis Pathway ◽

Stem Cell Pluripotency ◽

Extrinsic Apoptosis ◽

Related Proteins ◽

Cycle Regulation

AbstractLong non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides but not translated into proteins. LncRNAs regulate gene expressions at multiple levels, such as chromatin, transcription, and post-transcription. Further, lncRNAs participate in various biological processes such as cell differentiation, cell cycle regulation, and maintenance of stem cell pluripotency. We have previously reported that lncRNAs are closely related to programmed cell death (PCD), which includes apoptosis, autophagy, necroptosis, and ferroptosis. Overexpression of lncRNA can suppress the extrinsic apoptosis pathway by downregulating of membrane receptors and protect tumor cells by inhibiting the expression of necroptosis-related proteins. Some lncRNAs can also act as competitive endogenous RNA to prevent oxidation, thereby inhibiting ferroptosis, while some are known to activate autophagy. The relationship between lncRNA and PCD has promising implications in clinical research, and reports have highlighted this relationship in various cancers such as non-small cell lung cancer and gastric cancer. This review systematically summarizes the advances in the understanding of the molecular mechanisms through which lncRNAs impact PCD.

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