“Dead Cells Talking”: The Silent Form of Cell Death Is Not so Quiet

After more than twenty years of research, the molecular events of apoptotic cell death can be succinctly stated; different pathways, activated by diverse signals, increase the activity of proteases called caspases that rapidly and irreversibly dismantle condemned cell by cleaving specific substrates. In this time the ideas that apoptosis protects us from tumourigenesis and that cancer chemotherapy works by inducing apoptosis also emerged. Currently, apoptosis research is shifting away from the intracellular events within the dying cell to focus on the effect of apoptotic cells on surrounding tissues. This is producing counterintuitive data showing that our understanding of the role of apoptosis in tumourigenesis and cancer therapy is too simple, with some interesting and provocative implications. Here, we will consider evidence supporting the idea that dying cells signal their presence to the surrounding tissue and, in doing so, elicit repair and regeneration that compensates for any loss of function caused by cell death. We will discuss evidence suggesting that cancer cell proliferation may be driven by inappropriate or corrupted tissue-repair programmes that are initiated by signals from apoptotic cells and show how this may dramatically modify how we view the role of apoptosis in both tumourigenesis and cancer therapy.

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The final step in programmed cell death: phagocytes carry apoptotic cells to the grave

Essays in Biochemistry ◽

10.1042/bse0390105 ◽

2003 ◽

Vol 39 ◽

pp. 105-117 ◽

Cited By ~ 136

Author(s):

Aimee M deCathelineau ◽

Peter M Henson

Keyword(s):

Cell Death ◽

Apoptotic Cell ◽

The Body ◽

Apoptotic Cells ◽

Cytokines And Chemokines ◽

Cell Clearance ◽

And Function ◽

Multicellular Organisms ◽

Dying Cells ◽

High Degree

As cells undergo apoptosis, they are recognized and removed from the body by phagocytes. This oft-overlooked yet critical final step in the cell-death programme protects tissues from exposure to the toxic contents of dying cells and also serves to prevent further tissue damage by stimulating production of anti-inflammatory cytokines and chemokines. The clearance of apoptotic-cell corpses occurs throughout the lifespan of multicellular organisms and is important for normal development during embryogenesis, the maintenance of normal tissue integrity and function, and the resolution of inflammation. Many of the signal-transduction molecules implicated in the phagocytosis of apoptotic cells appear to have a high degree of evolutionary conservation, and therefore the engulfment of apoptotic cells is likely to represent one of the most primitive forms of phagocytosis. With the realization that the signals that govern apoptotic-cell removal also serve to attenuate inflammation and the immune response, as well as initiate signals for tissue repair and remodelling in response to cell death, the study of apoptotic cell clearance is a field experiencing a dynamic increase in interest and momentum.

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Apoptosis in the lung: induction, clearance and detection

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00320.2007 ◽

2008 ◽

Vol 294 (4) ◽

pp. L601-L611 ◽

Cited By ~ 65

Author(s):

P. M. Henson ◽

R. M. Tuder

Keyword(s):

Cell Death ◽

Tissue Repair ◽

Alternative Explanation ◽

Apoptotic Cell ◽

Lung Cells ◽

Apoptotic Cells ◽

Local Responses ◽

Apoptotic Cell Clearance ◽

Cell Clearance ◽

Dying Cells

Apoptosis and other forms of programmed cell death are important contributors to lung pathophysiology. In this brief review, we discuss some of the implications of finding apoptotic cells in the lung and methods for their detection. The balance between induction of apoptosis and the normally highly efficient clearance of such cells shows that these are highly dynamic processes and suggests that abnormalities of apoptotic cell clearance may be an alternative explanation for their detection. Because recognition of apoptotic cells by other lung cells has additional effects on inflammation, immunity, and tissue repair, local responses to the dying cells may also have important consequences in addition to the cell death itself.

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Anti-apogens and anti-engulfens: monoclonal antibodies reveal specific antigens on apoptotic and engulfment cells during chicken embryonic development

Development ◽

10.1242/dev.120.6.1421 ◽

1994 ◽

Vol 120 (6) ◽

pp. 1421-1431 ◽

Cited By ~ 2

Author(s):

R.J. Rotello ◽

P.A. Fernandez ◽

J. Yuan

Keyword(s):

Cell Death ◽

Monoclonal Antibodies ◽

Programmed Cell Death ◽

Apoptotic Cell ◽

Cell Types ◽

Apoptotic Cells ◽

Specific Antigens ◽

Common Leukocyte Antigen ◽

Cell Death Mechanisms ◽

Dying Cells

We have isolated a group of monoclonal antibodies that specifically recognize either apoptotic or engulfment cells in the interdigit areas of chicken hind limb foot plates, and throughout the embryo. Ten of these antibodies (anti-apogens) detect epitopes on dying cells that colocalize to areas of programmed cell death, characterized by the presence of apoptotic cells and bodies with typical cellular and nuclear morphology. Our results indicate that cells destined to die, or that are in the process of dying, express specific antigens that are not detectable in or on the surface of living cells. The detection of these apoptotic cell antigens in other areas of programmed cell death throughout the chick embryo indicates that different cell types, which form specific tissues and organs, may utilize similar cell death mechanisms. Six of the monoclonal antibodies (antiengulfens) define a class of engulfment cells which contain various numbers of apoptotic cells and/or apoptotic bodies in areas of programmed cell death. The immunostaining pattern of the anti-engulfen R15F is similar to that of an antibody against a common leukocyte antigen, suggesting the participation of cells from the immune system in the removal of apoptotic cell debris. These novel monoclonal antibody markers for apoptotic and engulfment cells will provide new tools to assist the further understanding of developmental programmed cell death in vertebrates.

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Flipping the dogma – phosphatidylserine in non-apoptotic cell death

Cell Communication and Signaling ◽

10.1186/s12964-019-0437-0 ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 18

Author(s):

Inbar Shlomovitz ◽

Mary Speir ◽

Motti Gerlic

Keyword(s):

Cell Death ◽

Inflammatory Cell ◽

Unique Feature ◽

Apoptotic Cell ◽

Apoptotic Cells ◽

Complete Understanding ◽

Cell Death Pathways ◽

Regulated Cell Death ◽

Dying Cells ◽

Outer Plasma Membrane

Abstract The exposure of phosphatidylserine (PS) on the outer plasma membrane has long been considered a unique feature of apoptotic cells. Together with other “eat me” signals, it enables the recognition and phagocytosis of dying cells (efferocytosis), helping to explain the immunologically-silent nature of apoptosis. Recently, however, PS exposure has also been reported in non-apoptotic forms of regulated inflammatory cell death, such as necroptosis, challenging previous dogma. In this review, we outline the evidence for PS exposure in non-apoptotic cells and extracellular vesicles (EVs), and discuss possible mechanisms based on our knowledge of apoptotic-PS exposure. In addition, we examine the outcomes of non-apoptotic PS exposure, including the reversibility of cell death, efferocytosis, and consequent inflammation. By examining PS biology, we challenge the established approach of distinguishing apoptosis from other cell death pathways by AnnexinV staining of PS externalization. Finally, we re-evaluate how PS exposure is thought to define apoptosis as an immunologically silent process distinct from other non-apoptotic and inflammatory cell death pathways. Ultimately, we suggest that a complete understanding of how regulated cell death processes affect the immune system is far from being fully elucidated. Graphical abstract

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Lysosome Biogenesis Mediated by vps-18 Affects Apoptotic Cell Degradation in Caenorhabditis elegans

Molecular Biology of the Cell ◽

10.1091/mbc.e08-04-0441 ◽

2009 ◽

Vol 20 (1) ◽

pp. 21-32 ◽

Cited By ~ 39

Author(s):

Hui Xiao ◽

Didi Chen ◽

Zhou Fang ◽

Jing Xu ◽

Xiaojuan Sun ◽

...

Keyword(s):

Cell Death ◽

Caenorhabditis Elegans ◽

Programmed Cell Death ◽

Direct Evidence ◽

Apoptotic Cell ◽

Apoptotic Cells ◽

Lysosome Biogenesis ◽

Cell Corpse ◽

Lysosomal Protein

Appropriate clearance of apoptotic cells (cell corpses) is an important step of programmed cell death. Although genetic and biochemical studies have identified several genes that regulate the engulfment of cell corpses, how these are degraded after being internalized in engulfing cell remains elusive. Here, we show that VPS-18, the Caenorhabditis elegans homologue of yeast Vps18p, is critical to cell corpse degradation. VPS-18 is expressed and functions in engulfing cells. Deletion of vps-18 leads to significant accumulation of cell corpses that are not degraded properly. Furthermore, vps-18 mutation causes strong defects in the biogenesis of endosomes and lysosomes, thus affecting endosomal/lysosomal protein degradation. Importantly, we demonstrate that phagosomes containing internalized cell corpses are unable to fuse with lysosomes in vps-18 mutants. Our findings thus provide direct evidence for the important role of endosomal/lysosomal degradation in proper clearance of apoptotic cells during programmed cell death.

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Communicating with the dead: lipids, lipid mediators and extracellular vesicles

Biochemical Society Transactions ◽

10.1042/bst20160477 ◽

2018 ◽

Vol 46 (3) ◽

pp. 631-639 ◽

Cited By ~ 1

Author(s):

Andrew Devitt ◽

Helen R. Griffiths ◽

Ivana Milic

Keyword(s):

Cell Death ◽

Extracellular Vesicles ◽

Apoptotic Cell ◽

Cell Communication ◽

Extracellular Vesicle ◽

Lipid Mediators ◽

Effective Control ◽

The Dead ◽

Dying Cells

Apoptosis is a key event in the control of inflammation. However, for this to be successful, dying cells must efficiently and effectively communicate their presence to phagocytes to ensure timely removal of dying cells. Here, we consider apoptotic cell-derived extracellular vesicles and the role of contained lipids and lipid mediators in ensuring effective control of inflammation. We discuss key outstanding issues in the study of cell death and cell communication, and introduce the concept of the ‘active extracellular vesicle’ as a metabolically active and potentially changing intercellular communicator.

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The Role of Ceramide Metabolism and Signaling in the Regulation of Mitophagy and Cancer Therapy

Cancers ◽

10.3390/cancers13102475 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2475

Author(s):

Megan Sheridan ◽

Besim Ogretmen

Keyword(s):

Cancer Therapy ◽

Acyl Chain ◽

Fatty Acyl ◽

Fatty Acyl Chain ◽

Cancer Cell Proliferation ◽

Bioactive Lipids ◽

Cellular Functions ◽

Proliferation Response ◽

Ceramide Synthases

Sphingolipids are bioactive lipids responsible for regulating diverse cellular functions such as proliferation, migration, senescence, and death. These lipids are characterized by a long-chain sphingosine backbone amide-linked to a fatty acyl chain with variable length. The length of the fatty acyl chain is determined by specific ceramide synthases, and this fatty acyl length also determines the sphingolipid’s specialized functions within the cell. One function in particular, the regulation of the selective autophagy of mitochondria, or mitophagy, is closely regulated by ceramide, a key regulatory sphingolipid. Mitophagy alterations have important implications for cancer cell proliferation, response to chemotherapeutics, and mitophagy-mediated cell death. This review will focus on the alterations of ceramide synthases in cancer and sphingolipid regulation of lethal mitophagy, concerning cancer therapy.

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The Role of Herbal Bioactive Components in Mitochondria Function and Cancer Therapy

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/3868354 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Fangfang Tao ◽

Yanrong Zhang ◽

Zhiqian Zhang

Keyword(s):

Cancer Therapy ◽

Cancer Cell ◽

Apoptotic Cell ◽

Redox Status ◽

Cancer Therapies ◽

Bioactive Components ◽

Atp Production

Mitochondria are highly dynamic double-membrane organelles which play a well-recognized role in ATP production, calcium homeostasis, oxidation-reduction (redox) status, apoptotic cell death, and inflammation. Dysfunction of mitochondria has long been observed in a number of human diseases, including cancer. Targeting mitochondria metabolism in tumors as a cancer therapeutic strategy has attracted much attention for researchers in recent years due to the essential role of mitochondria in cancer cell growth, apoptosis, and progression. On the other hand, a series of studies have indicated that traditional medicinal herbs, including traditional Chinese medicines (TCM), exert their potential anticancer effects as an effective adjunct treatment for alleviating the systemic side effects of conventional cancer therapies, for reducing the risk of recurrence and cancer mortality and for improving the quality of patients’ life. An amazing feature of these structurally diverse bioactive components is that majority of them target mitochondria to provoke cancer cell-specific death program. The aim of this review is to summarize the in vitro and in vivo studies about the role of these herbs, especially their bioactive compounds in the modulation of the disturbed mitochondrial function for cancer therapy.

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Cytotoxicity, Antiproliferative Effects, and Apoptosis Induction of Methanolic Extract ofCynometra caulifloraLinn. Whole Fruit on Human Promyelocytic Leukemia HL-60 Cells

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/127373 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 5

Author(s):

T-Johari S. A. Tajudin ◽

Nashriyah Mat ◽

Abu Bakar Siti-Aishah ◽

A. Aziz M. Yusran ◽

Afnani Alwi ◽

...

Keyword(s):

Cell Death ◽

Methanolic Extract ◽

Apoptotic Cell ◽

Mouse Fibroblast ◽

Promyelocytic Leukemia ◽

Apoptotic Cell Death ◽

Apoptotic Cells ◽

3T3 Cells ◽

Nih 3T3 ◽

Nih 3T3 Cells

Methanolic extract ofCynometra cauliflorawhole fruit was assayed for cytotoxicity against the human promyelocytic leukemia HL-60 and the normal mouse fibroblast NIH/3T3 cell lines by using the MTT assay. The CD50of the extract for 72 hours was 0.9 μg/mL whereas the value for the cytotoxic drug vincristine was 0.2 μg/mL. The viability of the NIH/3T3 cells was at 80.0% when treated at 15.0 μg/mL. The extract inhibited HL-60 cell proliferation with dose dependence. AO/PI staining of HL-60 cells treated with the extract revealed that majority of cells were in the apoptotic cell death mode. Flow cytometry analysis of HL-60 cells treated at CD50of the extract showed that the early apoptotic cells were 31.0, 26.3 and 19.9% at 24, 48, and 72 hours treatment, respectively. The percentage of late apoptotic cells was increased from 62.0 at 24 hours to 64.1 and 70.2 at 48 and 72 hours, respectively. Meanwhile, percent of necrotic cells were 4.9, 6.6, and 8.5 at 24, 48, and 72 hours, respectively. This study has shown that the methanolic extract ofC. cauliflorawhole fruit was cytotoxic towards HL-60 cells and induced the cells into apoptotic cell death mode, but less cytotoxic towards NIH/3T3 cells.

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