Cell death after irradiation: How, when and why cells die
Michael C. Joiner, Albert J. van der Kogel in Basic Clinical Radiobiology, 2018
There is strong evidence that necrosis can also occur in a ‘programmed’ manner and constitute an alternative to apoptosis. Necroptosis refers to a specific form of programmed necrosis that is initiated by receptor-interacting protein kinase 3 (RIPK3) and other forms of programmed necrosis include the excitotoxicity of neurons. For example, induction of necrosis is dependent on cellular energy stores, such as NAD and ATP, and can be regulated by receptor signalling pathways. Furthermore, cell stress and cell signalling including oxidative stress, calcium levels and p53 activation have been shown to influence lysosomal membrane permeability. Permeabilization leads to intracellular acidification and release of various enzymes that can promote necrosis. Other distinct forms of non-apoptotic cell death that result from aberrant cell signalling have been identified. For example, ferroptosis is an iron-linked form of cell death that occurs when cells are unable to control iron-dependent reactive oxygen species generation. Although it is not clear how the cell controls necrosis, ferroptosis or other direct forms of programmed cell death following irradiation, the frequency with which this is observed varies among different cell types. This suggests that, just as for all the other forms of cell death, cellular pathways control the sensitivity of its activation.
The Role of Nanoparticles in Cancer Therapy through Apoptosis Induction
Hala Gali-Muhtasib, Racha Chouaib in Nanoparticle Drug Delivery Systems for Cancer Treatment, 2020
Two important molecular events that are exclusively considered as apoptosis hallmarks are (1) the externalization of phosphatidylserine and (2) activation of the caspase family of proteins [16, 18]. The morphological features of apoptosis are also different from necrosis [19, 20]. Apoptotic cells typically manifest extensive membrane blebbing, shrinkage of the cell, and nuclear condensation and fragmentation; while necrotic cells show membrane disruption, cell swelling, and decondensation of nuclei [19, 20]. However, recent reports have described a form of regulated necrosis, which is initiated via the activation of apoptotic cell signaling, but terminated with necrosis features [19]. Necroptosis is activated in response to the members of the “death receptor” subset of the TNF superfamily, without caspase activation. Necroptosis occurs in cells that express the kinase, RIPK3 to RIPK1. In a normal situation, CASP-8 suppresses the activation of RIPK3 onto RIPK1, and necroptosis is activated, followed by an infection with some viruses having caspase inhibitors. The most important difference between necroptosis and other types of cell death is the involvement of RIPK3/RIPK1 and the absence of caspase activity [21, 22].
Apoptosis and Cell Death
John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie in Basic Sciences Endocrine Surgery Rhinology, 2018
Necroptosis primarily appears to occur when caspases are inhibited, and one reason why apoptosis normally takes precedence over necroptosis is because active caspase 8 can cleave RIPK1 and RIPK3.9 Viral infection is a situation that can result in necroptosis because viruses inhibit caspases. Where tumour cells have become apoptosis resistant (perhaps through similar mechanisms to viral infection) necroptosis might be a useful way to eliminate tumour cells, although the consequences of the induction of inflammation to the tumour microenvironment will have to be considered.12, 13 While microscopically necroptosis appears as a swollen cell with formation of a balloon-like structure, known as oncosis, methods to identify necroptosis currently involve biochemical and fluorogenic assays on lysates or living cells, use of genetically modified mice or cells with RIPK3 or MLKL knockdown, or use of necrostatin and other more specific RIPK1 inhibitors to block the process.13
Development of neoantigens: from identification in cancer cells to application in cancer vaccines
Published in Expert Review of Vaccines, 2022
Nasim Ebrahimi, Maryam Akbari, Masoud Ghanaatian, Parichehr Roozbahani moghaddam, Samaneh Adelian, Marziyeh Borjian Boroujeni, Elnaz Yazdani, Amirhossein Ahmadi, Michael R. Hamblin
Necroptosis is an alternative mode of programmed cell death with features of both apoptosis and necrosis. In a similar manner to necrosis, it is considered to be pro-inflammatory, but is more effective in triggering the maturation of dendritic cells, cross-priming of cytotoxic T cells, and the secretion of IFN-gamma. This leads to better sensitization to tumor antigens contained within the necroptotic cancer cells [118]. Aaes et al. developed a method to produce necroptotic cells using direct dimerization of FADD combined with inducible expression of RIPK3 (receptor interacting protein kinase-3). These necroptotic cells enabled successful prophylactic vaccination of mice against CT26 colorectal tumors [118]. In another study by Turubanova et al. they used photodynamic therapy (PDT) mediated by two different photosensitizers, Photosens (PS) and Photodithazine (PD) against murine glioma GL261 and fibrosarcoma MCA205 cells. The type of cell death induced was analyzed by flow cytometry. The results indicated that PDT with PS or PD were novel ICD inducers, and could be used as a potential approach to prepare cancer vaccines [119].
LPS induces cardiomyocyte necroptosis through the Ripk3/Pgam5 signaling pathway
Published in Journal of Receptors and Signal Transduction, 2021
Guohua Fu, Binhao Wang, Bin He, Mingjun Feng, Yibo Yu
Necroptosis, a kind of regulated necrosis, is a new type of cell death that has been firstly described in the immune system. The following studies have further reported that the existence of necroptosis in cardiovascular disorder. For example, adverse ventricular remodeling after myocardial infarction has been found to be associated with necroptosis mediated by impaired autophagy [45]. Myocardial ischemia-reperfusion injury seems to be caused by necroptosis through a mechanism involving JNK-Bnip3 pathway [46]. Besides, diabetic cardiomyopathy is also mediated by necroptosis and this alteration seems to be linked to CaMKII signaling pathway [47]. In the present study, we found that septic cardiomyopathy is also featured by necroptosis which is regulated by the Ripk3/Pgam5 signaling pathway. Unlike other signaling pathways described above, Ripk3/Pgam5 is a classical necroptotic pathway [48]. Pgam5 is a phosphokinase that induces the phosphorylation of MLKL and the latter mediates the cellular membrane breakage and cell death [49]. In our study, we also found that the activity of MLKL was increased after exposure to LPS. Of note, more studies are required to further validate our findings in animal studies.
A novel necroptosis-related gene signature in acute myeloid leukemia
Published in Hematology, 2023
Weiyue Fang, Hongdou Lin, Junyi Chen, Wenjian Guo
Necroptosis is a newly identified type of programmed cell death that can be activated in the absence of apoptosis and triggered by the activation of death receptors [3]. Emerging studies indicate that receptor-interacting protein kinases 1 and 3 (RIPK1 and RIPK3) and downstream substrate pseudokinase mixed-lineage kinase domain-like (MLKL) play a crucial role in regulating necroptosis pathway [4]. The effects of necroptosis on cancer can be complex and paradoxical. On the one hand, many pivotal molecules in necroptotic signaling are downregulated in different types of cancer, such as breast cancer, colorectal cancer [5,6]. In this way, cancer cells may evade necroptosis and maintain proliferation. This suggests that necroptosis might help eliminate antiapoptotic tumor cells [7]. On the other hand, an increasing number of studies have also shown that necroptosis can promote tumor progression and metastasis by inducing an inflammatory response and creating a tumor-promoting microenvironment with elevated ROS production [8]. These changes in the tumor microenvironment can lead to genomic instability, ultimately accelerating malignant transformation [9,10].
Related Knowledge Centers
- Necrosis
- Apoptosis
- Immune System
- Caspase
- Crohn's Disease
- Pancreatitis
- Myocardial Infarction
- Tumor Necrosis Factor
- Damage-Associated Molecular Pattern
- Phagocytosis