scholarly journals The Role of Necroptosis: Biological Relevance and Its Involvement in Cancer

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 684
Author(s):  
Laura Della Torre ◽  
Angela Nebbioso ◽  
Hendrik G. Stunnenberg ◽  
Joost H. A. Martens ◽  
Vincenzo Carafa ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Fate ◽  
Intervention Strategy ◽  
Biological Relevance ◽  
Cellular Events ◽  
Regulated Cell Death ◽  
Independent Form ◽  
Cell Death Mechanisms ◽  
Cell Fate Control ◽  
Novel Therapeutic

Regulated cell death mechanisms are essential for the maintenance of cellular homeostasis. Evasion of cell death is one of the most important hallmarks of cancer. Necroptosis is a caspase independent form of regulated cell death, investigated as a novel therapeutic strategy to eradicate apoptosis resistant cancer cells. The process can be triggered by a variety of stimuli and is controlled by the activation of RIP kinases family as well as MLKL. The well-studied executor, RIPK1, is able to modulate key cellular events through the interaction with several proteins, acting as strategic crossroads of several molecular pathways. Little evidence is reported about its involvement in tumorigenesis. In this review, we summarize current studies on the biological relevance of necroptosis, its contradictory role in cancer and its function in cell fate control. Targeting necroptosis might be a novel therapeutic intervention strategy in anticancer therapies as a pharmacologically controllable event.

scholarly journals Cryo-EM structural analysis of FADD:Caspase-8 complexes defines the catalytic dimer architecture for co-ordinated control of cell fate

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Joanna L. Fox ◽  
Michelle A. Hughes ◽  
Xin Meng ◽  
Nikola A. Sarnowska ◽  
Ian R. Powley ◽  
...  
Keyword(s):  
Cell Death ◽  
Structural Analysis ◽  
Cell Fate ◽  
Catalytic Domain ◽  
Caspase 8 ◽  
Type I ◽  
Signaling Complex ◽  
Catalytic Domains ◽  
Regulated Cell Death ◽  
Death Effector

AbstractRegulated cell death is essential in development and cellular homeostasis. Multi-protein platforms, including the Death-Inducing Signaling Complex (DISC), co-ordinate cell fate via a core FADD:Caspase-8 complex and its regulatory partners, such as the cell death inhibitor c-FLIP. Here, using electron microscopy, we visualize full-length procaspase-8 in complex with FADD. Our structural analysis now reveals how the FADD-nucleated tandem death effector domain (tDED) helical filament is required to orientate the procaspase-8 catalytic domains, enabling their activation via anti-parallel dimerization. Strikingly, recruitment of c-FLIPS into this complex inhibits Caspase-8 activity by altering tDED triple helix architecture, resulting in steric hindrance of the canonical tDED Type I binding site. This prevents both Caspase-8 catalytic domain assembly and tDED helical filament elongation. Our findings reveal how the plasticity, composition and architecture of the core FADD:Caspase-8 complex critically defines life/death decisions not only via the DISC, but across multiple key signaling platforms including TNF complex II, the ripoptosome, and RIPK1/RIPK3 necrosome.

Abstract P419: A Systematic Characterization of Brain Endothelial Cell Death in Intracerebral Hemorrhage

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Maulana Ikhsan ◽  
Marietta Zille
Keyword(s):  
Cell Death ◽  
Intracerebral Hemorrhage ◽  
Brain Tissue ◽  
Vascular Integrity ◽  
Regulated Cell Death ◽  
Injury Mechanisms ◽  
Endothelial Cell Death ◽  
Cell Death Mechanisms ◽  
Underlying Mechanisms

Introduction: Intracerebral hemorrhage (ICH) is a type of stroke caused by the loss of vascular integrity leading to bleeding within the brain tissue. Hematoma-derived factors cause secondary injury mechanisms such as cell death days to weeks after the event and in regions distant from the primary insult. Increasing evidence suggests that hemoglobin released by the hematoma is one of the major contributors to neuronal injury in ICH. To date, it is unclear whether brain endothelial cells (EC) are similarly vulnerable to hemolysis products and undergo regulated cell death. Hypothesis: We hypothesized that brain EC undergo multiple, different modes of cell death after ICH and that the underlying mechanisms are different compared to neurons. Methods: We systematically investigated cell death mechanisms in brain EC after exposure to the hemolysis product hemin. We used chemical inhibitors of apoptosis, autophagy, ferroptosis, necroptosis, and parthanatos and assessed biochemical markers of these cell death modes. Results: Brain EC viability was concentration-dependently decreased, starting at higher hemin concentrations than neurons. Treatment of EC with ferroptosis inhibitors protective against hemin toxicity in neurons and against ICH in vivo showed that only N-acetylcysteine and deferoxamine protected brain EC, while ferrostatin-1 and U0126 did not abrogate EC death. The autophagy inhibitor bafilomycin A1 also reduced EC death and hemin increased the expression of the autophagy marker LC3. While inhibitors against apoptosis and parthanatos were not effective, the necroptosis inhibitor GSK872 demonstrated a partial protective effect. Conclusions: Our data suggest that ICH induces different mechanisms of death in EC (ferroptosis and autophagy) compared to neurons (ferroptosis and necroptosis) and may thus warrant a combinatorial therapeutic approach. Further investigations in human and ovine ICH brain tissue are ongoing.

scholarly journals Cdk8 Kinase Module: A Mediator of Life and Death Decisions in Times of Stress

2021 ◽  
Vol 9 (10) ◽  
pp. 2152
Author(s):  
Brittany Friedson ◽  
Katrina F. Cooper
Keyword(s):  
Cell Death ◽  
Rna Polymerase Ii ◽  
Cell Fate ◽  
Ubiquitin Proteasome System ◽  
Mitochondrial Morphology ◽  
Atp Production ◽  
Cell Fate Decisions ◽  
Regulated Cell Death ◽  
Cyclin C ◽  
Convergence Point

The Cdk8 kinase module (CKM) of the multi-subunit mediator complex plays an essential role in cell fate decisions in response to different environmental cues. In the budding yeast S. cerevisiae, the CKM consists of four conserved subunits (cyclin C and its cognate cyclin-dependent kinase Cdk8, Med13, and Med12) and predominantly negatively regulates a subset of stress responsive genes (SRG’s). Derepression of these SRG’s is accomplished by disassociating the CKM from the mediator, thus allowing RNA polymerase II-directed transcription. In response to cell death stimuli, cyclin C translocates to the mitochondria where it induces mitochondrial hyper-fission and promotes regulated cell death (RCD). The nuclear release of cyclin C requires Med13 destruction by the ubiquitin-proteasome system (UPS). In contrast, to protect the cell from RCD following SRG induction induced by nutrient deprivation, cyclin C is rapidly destroyed by the UPS before it reaches the cytoplasm. This enables a survival response by two mechanisms: increased ATP production by retaining reticular mitochondrial morphology and relieving CKM-mediated repression on autophagy genes. Intriguingly, nitrogen starvation also stimulates Med13 destruction but through a different mechanism. Rather than destruction via the UPS, Med13 proteolysis occurs in the vacuole (yeast lysosome) via a newly identified Snx4-assisted autophagy pathway. Taken together, these findings reveal that the CKM regulates cell fate decisions by both transcriptional and non-transcriptional mechanisms, placing it at a convergence point between cell death and cell survival pathways.

scholarly journals Regulated cell death pathways in doxorubicin-induced cardiotoxicity

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Effimia Christidi ◽  
Liam R. Brunham
Keyword(s):  
Cell Death ◽  
Therapeutic Agents ◽  
Chemotherapeutic Drug ◽  
Cell Death Pathways ◽  
Recent Advances ◽  
Regulated Cell Death ◽  
Potent Drug ◽  
Novel Therapeutic

AbstractDoxorubicin is a chemotherapeutic drug used for the treatment of various malignancies; however, patients can experience cardiotoxic effects and this has limited the use of this potent drug. The mechanisms by which doxorubicin kills cardiomyocytes has been elusive and despite extensive research the exact mechanisms remain unknown. This review focuses on recent advances in our understanding of doxorubicin induced regulated cardiomyocyte death pathways including autophagy, ferroptosis, necroptosis, pyroptosis and apoptosis. Understanding the mechanisms by which doxorubicin leads to cardiomyocyte death may help identify novel therapeutic agents and lead to more targeted approaches to cardiotoxicity testing.

scholarly journals Pkh1p-Ypk1p and Pkh1p-Sch9p Pathways Are Activated by Acetic Acid to Induce a Mitochondrial-Dependent Regulated Cell Death

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
António Rego ◽  
Filipa Mendes ◽  
Vítor Costa ◽  
Susana Rodrigues Chaves ◽  
Manuela Côrte-Real
Keyword(s):  
Cell Death ◽  
Acetic Acid ◽  
Cell Survival ◽  
Cell Fate ◽  
Negative Regulator ◽  
Mitochondrial Outer Membrane ◽  
Mitochondrial Outer Membrane Permeabilization ◽  
Double Deletion ◽  
Regulated Cell Death ◽  
Single Deletion

The yeast Saccharomyces cerevisiae undergoes a mitochondrial-dependent regulated cell death (RCD) exhibiting typical markers of mammalian apoptosis. We have previously shown that ceramide production contributes to RCD induced by acetic acid and is involved in mitochondrial outer membrane permeabilization and cytochrome c release, especially through hydrolysis of complex sphingolipids catalyzed by Isc1p. Recently, we also showed that Sch9p regulates the translocation of Isc1p from the endoplasmic reticulum into mitochondria, perturbing sphingolipid balance and determining cell fate. In this study, we addressed the role of other signaling proteins in acetic acid-induced RCD. We found that single deletion of PKH1 or YPK1, as shown for SCH9 and ISC1, leads to an increase in cell survival in response to acetic acid and that Pkh1/2p-dependent phosphorylation of Ypk1p and Sch9p increases under these conditions. These results indicate that Pkh1p regulates acetic acid-induced RCD through Ypk1p and Sch9p. In addition, our results suggest that Pkh1p-Ypk1p is necessary for isc1Δ resistance to acetic acid-induced RCD. Moreover, double deletion of ISC1 and PKH1 has a drastic effect on cell survival associated with increased ROS accumulation and release of cytochrome c, which is counteracted by overexpression of the PKA pathway negative regulator PDE2. Overall, our results suggest that Pkh1p-Ypk1p and Pkh1p-Sch9p pathways contribute to RCD induced by acetic acid.

scholarly journals Guidelines for evaluating myocardial cell death

2019 ◽  
Vol 317 (5) ◽  
pp. H891-H922 ◽  
Author(s):  
Paras K. Mishra ◽  
Adriana Adameova ◽  
Joseph A. Hill ◽  
Christopher P. Baines ◽  
Peter M. Kang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cell Death ◽  
Best Practices ◽  
Cardiac Remodeling ◽  
Myocardial Cell ◽  
Autophagic Cell Death ◽  
Multiple Forms ◽  
Regulated Cell Death ◽  
Fundamental Process ◽  
Cell Death Mechanisms

Cell death is a fundamental process in cardiac pathologies. Recent studies have revealed multiple forms of cell death, and several of them have been demonstrated to underlie adverse cardiac remodeling and heart failure. With the expansion in the area of myocardial cell death and increasing concerns over rigor and reproducibility, it is important and timely to set a guideline for the best practices of evaluating myocardial cell death. There are six major forms of regulated cell death observed in cardiac pathologies, namely apoptosis, necroptosis, mitochondrial-mediated necrosis, pyroptosis, ferroptosis, and autophagic cell death. In this article, we describe the best methods to identify, measure, and evaluate these modes of myocardial cell death. In addition, we discuss the limitations of currently practiced myocardial cell death mechanisms. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/guidelines-for-evaluating-myocardial-cell-death/ .

scholarly journals The Role of Neutrophil NETosis in Organ Injury: Novel Inflammatory Cell Death Mechanisms

Inflammation ◽  
2020 ◽  
Vol 43 (6) ◽  
pp. 2021-2032 ◽  
Author(s):  
Zhen Cahilog ◽  
Hailin Zhao ◽  
Lingzhi Wu ◽  
Azeem Alam ◽  
Shiori Eguchi ◽  
...  
Keyword(s):  
Cell Death ◽  
Organ Injury ◽  
Microbial Function ◽  
Regulated Cell Death ◽  
Therapeutic Measures ◽  
Unexplored Area ◽  
Decondensed Chromatin ◽  
Cell Death Mechanisms ◽  
The Brain

Abstract NETosis is a type of regulated cell death dependent on the formation of neutrophil extracellular traps (NET), where net-like structures of decondensed chromatin and proteases are produced by polymorphonuclear (PMN) granulocytes. These structures immobilise pathogens and restrict them with antimicrobial molecules, thus preventing their spread. Whilst NETs possess a fundamental anti-microbial function within the innate immune system under physiological circumstances, increasing evidence also indicates that NETosis occurs in the pathogenic process of other disease type, including but not limited to atherosclerosis, airway inflammation, Alzheimer’s and stroke. Here, we reviewed the role of NETosis in the development of organ injury, including injury to the brain, lung, heart, kidney, musculoskeletal system, gut and reproductive system, whilst therapeutic agents in blocking injuries induced by NETosis in its primitive stages were also discussed. This review provides novel insights into the involvement of NETosis in different organ injuries, and whilst potential therapeutic measures targeting NETosis remain a largely unexplored area, these warrant further investigation.

scholarly journals Deubiquitinases: Modulators of Different Types of Regulated Cell Death

2021 ◽  
Vol 22 (9) ◽  
pp. 4352
Author(s):  
Choong-Sil Lee ◽  
Seungyeon Kim ◽  
Gyuho Hwang ◽  
Jaewhan Song
Keyword(s):  
Cell Death ◽  
Cell Fate ◽  
Translational Regulation ◽  
Molecular Mechanisms ◽  
Regulatory Mechanisms ◽  
Therapeutic Targeting ◽  
Multiple Modalities ◽  
Physiological Processes ◽  
Regulated Cell Death ◽  
Different Types

The mechanisms and physiological implications of regulated cell death (RCD) have been extensively studied. Among the regulatory mechanisms of RCD, ubiquitination and deubiquitination enable post-translational regulation of signaling by modulating substrate degradation and signal transduction. Deubiquitinases (DUBs) are involved in diverse molecular pathways of RCD. Some DUBs modulate multiple modalities of RCD by regulating various substrates and are powerful regulators of cell fate. However, the therapeutic targeting of DUB is limited, as the physiological consequences of modulating DUBs cannot be predicted. In this review, the mechanisms of DUBs that regulate multiple types of RCD are summarized. This comprehensive summary aims to improve our understanding of the complex DUB/RCD regulatory axis comprising various molecular mechanisms for diverse physiological processes. Additionally, this review will enable the understanding of the advantages of therapeutic targeting of DUBs and developing strategies to overcome the side effects associated with the therapeutic applications of DUB modulators.

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