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Trends in Cancer May 2023Induction of cell death is inexorably linked with cancer therapy, but this can also initiate wound-healing processes that have been linked to cancer progression and... (Review)
Review
Induction of cell death is inexorably linked with cancer therapy, but this can also initiate wound-healing processes that have been linked to cancer progression and therapeutic resistance. Here we describe the contribution of apoptosis and the lytic cell death pathways in the response to therapy (including chemotherapy and immunotherapy). We also discuss how necroptosis, pyroptosis, and ferroptosis function to promote tumor immunogenicity, along with emerging findings that these same forms of death can paradoxically contribute to immune suppression and tumor progression. Understanding the duality of cell death in cancer may allow for the development of therapeutics that shift the balance towards regression.
Topics: Humans; Cell Death; Apoptosis; Pyroptosis; Neoplasms; Immunity
PubMed: 36841748
DOI: 10.1016/j.trecan.2023.02.001 -
Frontiers in Immunology 2022The demise of cells in various ways enables the body to clear unwanted cells. Studies over the years revealed distinctive molecular mechanisms and functional... (Review)
Review
The demise of cells in various ways enables the body to clear unwanted cells. Studies over the years revealed distinctive molecular mechanisms and functional consequences of several key cell death pathways. Currently, the most intensively investigated programmed cell death (PCD) includes apoptosis, necroptosis, pyroptosis, ferroptosis, PANoptosis, and autophagy, which has been discovered to play crucial roles in modulating the immunosuppressive tumor microenvironment (TME) and determining clinical outcomes of the cancer therapeutic approaches. PCD can play dual roles, either pro-tumor or anti-tumor, partly depending on the intracellular contents released during the process. PCD also regulates the enrichment of effector or regulatory immune cells, thus participating in fine-tuning the anti-tumor immunity in the TME. In this review, we focused primarily on apoptosis, necroptosis, pyroptosis, ferroptosis, PANoptosis, and autophagy, discussed the released molecular messengers participating in regulating their intricate crosstalk with the immune response in the TME, and explored the immunological consequence of PCD and its implications in future cancer therapy developments.
Topics: Apoptosis; Ferroptosis; Humans; Necroptosis; Neoplasms; Pyroptosis; Tumor Microenvironment
PubMed: 35432318
DOI: 10.3389/fimmu.2022.847345 -
Journal of Immunology (Baltimore, Md. :... Nov 2022Innate immunity is the first response to protect against pathogens and cellular insults. Pattern recognition receptors sense pathogen- and damage-associated molecular... (Review)
Review
Innate immunity is the first response to protect against pathogens and cellular insults. Pattern recognition receptors sense pathogen- and damage-associated molecular patterns and induce an innate immune response characterized by inflammation and programmed cell death (PCD). In-depth characterization of innate immune PCD pathways has highlighted significant cross-talk. Recent advances led to the identification of a unique inflammatory PCD modality called PANoptosis, which is regulated by multifaceted PANoptosome complexes that are assembled by integrating components from other PCD pathways. The totality of biological effects observed in PANoptosis cannot be accounted for by any other PCD pathway alone. In this review, we briefly describe mechanisms of innate immune cell death, including molecular mechanisms of PANoptosis activation and regulation. We also highlight the PANoptosomes identified to date and provide an overview of the implications of PANoptosis in disease and therapeutic targeting. Improved understanding of innate immune-mediated cell death, PANoptosis, is critical to inform the next generation of treatment strategies.
Topics: Apoptosis; Cell Death; Immunity, Innate
PubMed: 36253067
DOI: 10.4049/jimmunol.2200508 -
EBioMedicine Jul 2017Cellular senescence entails essentially irreversible replicative arrest, apoptosis resistance, and frequently acquisition of a pro-inflammatory, tissue-destructive... (Review)
Review
Cellular senescence entails essentially irreversible replicative arrest, apoptosis resistance, and frequently acquisition of a pro-inflammatory, tissue-destructive senescence-associated secretory phenotype (SASP). Senescent cells accumulate in various tissues with aging and at sites of pathogenesis in many chronic diseases and conditions. The SASP can contribute to senescence-related inflammation, metabolic dysregulation, stem cell dysfunction, aging phenotypes, chronic diseases, geriatric syndromes, and loss of resilience. Delaying senescent cell accumulation or reducing senescent cell burden is associated with delay, prevention, or alleviation of multiple senescence-associated conditions. We used a hypothesis-driven approach to discover pro-survival Senescent Cell Anti-apoptotic Pathways (SCAPs) and, based on these SCAPs, the first senolytic agents, drugs that cause senescent cells to become susceptible to their own pro-apoptotic microenvironment. Several senolytic agents, which appear to alleviate multiple senescence-related phenotypes in pre-clinical models, are beginning the process of being translated into clinical interventions that could be transformative.
Topics: Aging; Animal Experimentation; Animals; Apoptosis; Biomarkers; Cellular Senescence; Chronic Disease; Disease Susceptibility; Drug Discovery; Humans; Phenotype; Secretory Pathway; Signal Transduction; Translational Research, Biomedical
PubMed: 28416161
DOI: 10.1016/j.ebiom.2017.04.013 -
Experimental & Molecular Medicine Aug 2023Mitochondria, ubiquitous double-membrane-bound organelles, regulate energy production, support cellular activities, harbor metabolic pathways, and, paradoxically,... (Review)
Review
Mitochondria, ubiquitous double-membrane-bound organelles, regulate energy production, support cellular activities, harbor metabolic pathways, and, paradoxically, mediate cell fate. Evidence has shown mitochondria as points of convergence for diverse cell death-inducing pathways that trigger the various mechanisms underlying apoptotic and nonapoptotic programmed cell death. Thus, dysfunctional cellular pathways eventually lead or contribute to various age-related diseases, such as neurodegenerative, cardiovascular and metabolic diseases. Thus, mitochondrion-associated programmed cell death-based treatments show great therapeutic potential, providing novel insights in clinical trials. This review discusses mitochondrial quality control networks with activity triggered by stimuli and that maintain cellular homeostasis via mitohormesis, the mitochondrial unfolded protein response, and mitophagy. The review also presents details on various forms of mitochondria-associated programmed cell death, including apoptosis, necroptosis, ferroptosis, pyroptosis, parthanatos, and paraptosis, and highlights their involvement in age-related disease pathogenesis, collectively suggesting therapeutic directions for further research.
Topics: Apoptosis; Mitochondria; Cell Death; Pyroptosis
PubMed: 37612409
DOI: 10.1038/s12276-023-01046-5 -
Ageing Research Reviews Sep 2015Programmed cell death (PCD) pathways, including apoptosis and regulated necrosis, are required for normal cell turnover and tissue homeostasis. Mis-regulation of PCD is... (Review)
Review
Programmed cell death (PCD) pathways, including apoptosis and regulated necrosis, are required for normal cell turnover and tissue homeostasis. Mis-regulation of PCD is increasingly implicated in aging and aging-related disease. During aging the cell turnover rate declines for several highly-mitotic tissues. Aging-associated disruptions in systemic and inter-cell signaling combined with cell-autonomous damage and mitochondrial malfunction result in increased PCD in some cell types, and decreased PCD in other cell types. Increased PCD during aging is implicated in immune system decline, skeletal muscle wasting (sarcopenia), loss of cells in the heart, and neurodegenerative disease. In contrast, cancer cells and senescent cells are resistant to PCD, enabling them to increase in abundance during aging. PCD pathways limit life span in fungi, but whether PCD pathways normally limit adult metazoan life span is not yet clear. PCD is regulated by a balance of negative and positive factors, including the mitochondria, which are particularly subject to aging-associated malfunction.
Topics: Aging; Animals; Apoptosis; Cell Death; Cellular Senescence; Homeostasis; Humans; Neurodegenerative Diseases
PubMed: 25862945
DOI: 10.1016/j.arr.2015.04.002 -
Biological Research Mar 2019Hypoxia microenvironment plays a crucial role during tumor progression and it tends to exhibit poor prognosis and make resistant to various conventional therapies....
BACKGROUND/AIMS
Hypoxia microenvironment plays a crucial role during tumor progression and it tends to exhibit poor prognosis and make resistant to various conventional therapies. HIF-1α acts as an important transcriptional regulator directly or indirectly associated with genes involved in cell proliferation, angiogenesis, apoptosis and energy metabolism during tumor progression in hypoxic microenvironment. This study was aimed to investigate the expression pattern of the hypoxia associated genes and their association during breast cancer progression under hypoxic microenvironment in breast cancer cells.
METHODS
Cell proliferation in MCF-7 and MDA-MB-231 cell lines treated with different concentration of CoCl was analyzed by MTT assay. Flow cytometry was performed to check cell cycle distribution, whereas cell morphology was examined by phase contrast microscopy in both the cells during hypoxia induction. Expression of hypoxia associated genes HIF-1α, VEGF, p53 and BAX were determined by semiquantitative RT-PCR and real-time PCR. Western blotting was performed to detect the expression at protein level.
RESULTS
Our study revealed that cell proliferation in CoCl treated breast cancer cells were concentration dependent and varies with different cell types, further increase in CoCl concentration leads to apoptotic cell death. Further, accumulation of p53 protein in response to hypoxia as compare to normoxia showed that induction of p53 in breast cancer cells is HIF-1α dependent. HIF-1α dependent BAX expression during hypoxia revealed that after certain extent of hypoxia induction, over expression of BAX conquers the effect of anti-apoptotic proteins and ultimately leads to apoptosis in breast cancer cells.
CONCLUSION
In conclusion our results clearly indicate that CoCl simulated hypoxia induce the accumulation of HIF-1α protein and alter the expression of hypoxia associated genes involved in angiogenesis and apoptosis.
Topics: Apoptosis; Blotting, Western; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Cobalt; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Transfection
PubMed: 30876462
DOI: 10.1186/s40659-019-0221-z -
Molecular Therapy : the Journal of the... Jan 2021Ferroptosis is primarily caused by intracellular iron catalytic activity and lipid peroxidation. The potential interplay between ferroptosis and apoptosis remains poorly...
Ferroptosis is primarily caused by intracellular iron catalytic activity and lipid peroxidation. The potential interplay between ferroptosis and apoptosis remains poorly understood. Here, we show that the expression of a nuclear long non-coding RNA (lncRNA), LINC00618, is reduced in human leukemia and strongly increased by vincristine (VCR) treatment. Furthermore, LINC00618 promotes apoptosis by increasing the levels of BCL2-Associated X (BAX) and cleavage of caspase-3. LINC00618 also accelerates ferroptosis by increasing the levels of lipid reactive oxygen species (ROS) and iron, two surrogate markers of ferroptosis, and decreasing the expression of solute carrier family 7 member 11 (SLC7A11). Interestingly, VCR-induced ferroptosis and apoptosis are promoted by LINC00618, and LINC00618 accelerates ferroptosis in a manner dependent upon apoptosis. LINC00618 attenuates the expression of lymphoid-specific helicase (LSH), and LSH enhances the transcription of SLC7A11 after the recruitment to the promoter regions of SLC7A11, further inhibiting ferroptosis. Knowledge of these mechanisms demonstrates that lncRNAs related to ferroptosis and apoptosis are critical to leukemogenesis and chemotherapy.
Topics: Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Cell Line, Tumor; Cell Nucleus; Ferroptosis; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Protein Binding; RNA, Long Noncoding; Reactive Oxygen Species
PubMed: 33002417
DOI: 10.1016/j.ymthe.2020.09.024 -
The American Journal of Pathology Jan 1995The historical development of the cell death concept is reviewed, with special attention to the origin of the terms necrosis, coagulation necrosis, autolysis,... (Review)
Review
The historical development of the cell death concept is reviewed, with special attention to the origin of the terms necrosis, coagulation necrosis, autolysis, physiological cell death, programmed cell death, chromatolysis (the first name of apoptosis in 1914), karyorhexis, karyolysis, and cell suicide, of which there are three forms: by lysosomes, by free radicals, and by a genetic mechanism (apoptosis). Some of the typical features of apoptosis are discussed, such as budding (as opposed to blebbing and zeiosis) and the inflammatory response. For cell death not by apoptosis the most satisfactory term is accidental cell death. Necrosis is commonly used but it is not appropriate, because it does not indicate a form of cell death but refers to changes secondary to cell death by any mechanism, including apoptosis. Abundant data are available on one form of accidental cell death, namely ischemic cell death, which can be considered an entity of its own, caused by failure of the ionic pumps of the plasma membrane. Because ischemic cell death (in known models) is accompanied by swelling, the name oncosis is proposed for this condition. The term oncosis (derived from ónkos, meaning swelling) was proposed in 1910 by von Reckling-hausen precisely to mean cell death with swelling. Oncosis leads to necrosis with karyolysis and stands in contrast to apoptosis, which leads to necrosis with karyorhexis and cell shrinkage.
Topics: Animals; Apoptosis; Cell Death; Humans; Necrosis
PubMed: 7856735
DOI: No ID Found -
International Journal of Molecular... Oct 2023PANoptosis is a newly defined programmed cell death (PCD) triggered by a series of stimuli, and it engages three well-learned PCD forms (pyroptosis, apoptosis,... (Review)
Review
PANoptosis is a newly defined programmed cell death (PCD) triggered by a series of stimuli, and it engages three well-learned PCD forms (pyroptosis, apoptosis, necroptosis) concomitantly. Normally, cell death is recognized as a strategy to eliminate unnecessary cells, inhibit the proliferation of invaded pathogens and maintain homeostasis; however, vigorous cell death can cause excessive inflammation and tissue damage. Acute lung injury (ALI) and chronic obstructive pulmonary syndrome (COPD) exacerbation is related to several pathogens (e.g., influenza A virus, SARS-CoV-2) known to cause PANoptosis. An understanding of the mechanism and specific regulators may help to address the pathological systems of these diseases. This review presents our understanding of the potential mechanism of PANoptosis and the role of PANoptosis in different pulmonary diseases.
Topics: Humans; Apoptosis; Cell Death; Acute Lung Injury; Homeostasis; Inflammation; Pyroptosis
PubMed: 37895022
DOI: 10.3390/ijms242015343