Pub Date : 2024-07-23DOI: 10.3389/fceld.2024.1422224
I. Deidda, R. Russo, Nadia Lampiasi, F. Zito, R. Bonaventura
In addition to many industrial activities that release pollutants in coastal areas, numerous human behaviors contribute to climate change, inducing global warming, which can also reshape the environmental impacts of some pollutants. Therefore, it is extremely important to develop new tools that can detect pollutants and environmental changes quickly and easily with high levels of sensitivity. The sea urchin embryo is a well-known model used worldwide in many research fields, including marine ecotoxicology, as a huge range of contaminants can affect its embryonic development with species-specific sensitivity. Morphological abnormalities are already considered biomarkers to evaluate the effects of pollutants, and, indeed, the sea urchin has long been used as one of the key species in a battery of bioassays to assess the toxicity of many pollutants and dredged sediments. At the cellular level, the molecular mechanisms activated against a stress agent constitute what is known as the “cell stress response,” analyzed here within a whole organism, namely, the sea urchin embryo. In this minireview, we have reported the available molecular biomarkers linked to morphological abnormalities and the genes affected by environmental changes and emerging pollutants, highlighting those studies that use high-throughput screening approaches to evaluate the effects of environmental conditions on sea urchin embryos.
{"title":"The sea urchin embryo and the cell stress responses: new perspectives","authors":"I. Deidda, R. Russo, Nadia Lampiasi, F. Zito, R. Bonaventura","doi":"10.3389/fceld.2024.1422224","DOIUrl":"https://doi.org/10.3389/fceld.2024.1422224","url":null,"abstract":"In addition to many industrial activities that release pollutants in coastal areas, numerous human behaviors contribute to climate change, inducing global warming, which can also reshape the environmental impacts of some pollutants. Therefore, it is extremely important to develop new tools that can detect pollutants and environmental changes quickly and easily with high levels of sensitivity. The sea urchin embryo is a well-known model used worldwide in many research fields, including marine ecotoxicology, as a huge range of contaminants can affect its embryonic development with species-specific sensitivity. Morphological abnormalities are already considered biomarkers to evaluate the effects of pollutants, and, indeed, the sea urchin has long been used as one of the key species in a battery of bioassays to assess the toxicity of many pollutants and dredged sediments. At the cellular level, the molecular mechanisms activated against a stress agent constitute what is known as the “cell stress response,” analyzed here within a whole organism, namely, the sea urchin embryo. In this minireview, we have reported the available molecular biomarkers linked to morphological abnormalities and the genes affected by environmental changes and emerging pollutants, highlighting those studies that use high-throughput screening approaches to evaluate the effects of environmental conditions on sea urchin embryos.","PeriodicalId":73072,"journal":{"name":"Frontiers in cell death","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141813661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-15DOI: 10.3389/fceld.2024.1423805
Y. Shan, B. Mollereau
The exploration of multiple regulated cell death (RCD) pathways and the recognition that several cell death-related proteins, including caspases, serve non-canonical roles have significantly expanded and diversified cell death research. Caspases not only cleave cellular substrates, triggering apoptosis, but also impact essential processes such as cellular differentiation, proliferation, growth, and migration. These novel caspase-dependent regulatory networks are extensively studied during development, with Drosophila providing a diverse range of developmental models for investigating these phenomena. Moreover, recent insights into the non-canonical functions of cell death proteins have highlighted their pivotal role in cancer aggressiveness. Ultimately, understanding these non-canonical functions sheds light on the intricate connections between RCD pathways and their significance in promoting anti-oncogenic responses.
{"title":"Non-canonical functions of regulated cell death machinery regulate cellular growth, invasion and the interplay between cell death modalities","authors":"Y. Shan, B. Mollereau","doi":"10.3389/fceld.2024.1423805","DOIUrl":"https://doi.org/10.3389/fceld.2024.1423805","url":null,"abstract":"The exploration of multiple regulated cell death (RCD) pathways and the recognition that several cell death-related proteins, including caspases, serve non-canonical roles have significantly expanded and diversified cell death research. Caspases not only cleave cellular substrates, triggering apoptosis, but also impact essential processes such as cellular differentiation, proliferation, growth, and migration. These novel caspase-dependent regulatory networks are extensively studied during development, with Drosophila providing a diverse range of developmental models for investigating these phenomena. Moreover, recent insights into the non-canonical functions of cell death proteins have highlighted their pivotal role in cancer aggressiveness. Ultimately, understanding these non-canonical functions sheds light on the intricate connections between RCD pathways and their significance in promoting anti-oncogenic responses.","PeriodicalId":73072,"journal":{"name":"Frontiers in cell death","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141647978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-05DOI: 10.3389/fceld.2024.1337724
YingChu Gu, ZeRui Wu, Heng Xie, Tao Fang, Qiufei Wang, Ye Gu
Periprosthetic osteolysis is a difficult-to-treat complication of arthroplasty. The pathological mechanisms of periprosthetic osteolysis are mainly weakened function of osteoblasts and excessive activation of osteoclasts. Many studies have demonstrated that the imbalance between the formation of bone by osteoblasts and the absorption of bone by osteoclasts is the direct cause of osteolytic diseases. Autophagy, as an important self-protective cellular mechanism, has significant effects on the regulation of osteoblast function, such as osteoblast differentiation, proliferation, and apoptosis. Osteoblasts, which play an important role in maintaining bone homeostasis, have attracted increasing attention in recent years. Up till now, Several signaling pathways have been proved to regulate autophagy of osteoblasts, including the AMPK, NF-κB, FoxO3 and other signaling pathways. This article reviews the recent progress in understanding osteoblast autophagy and mitophagy in the context of periprosthetic osteolysis and the signaling pathways which are involved in these processes. By summarizing previous studies describing the mechanism underlying osteoblast autophagy, we wish to contribute new therapeutic ideas and potential therapeutic targets for periprosthetic osteolysis.
{"title":"Regulatory signaling pathways of osteoblast autophagy in periprosthetic osteolysis","authors":"YingChu Gu, ZeRui Wu, Heng Xie, Tao Fang, Qiufei Wang, Ye Gu","doi":"10.3389/fceld.2024.1337724","DOIUrl":"https://doi.org/10.3389/fceld.2024.1337724","url":null,"abstract":"Periprosthetic osteolysis is a difficult-to-treat complication of arthroplasty. The pathological mechanisms of periprosthetic osteolysis are mainly weakened function of osteoblasts and excessive activation of osteoclasts. Many studies have demonstrated that the imbalance between the formation of bone by osteoblasts and the absorption of bone by osteoclasts is the direct cause of osteolytic diseases. Autophagy, as an important self-protective cellular mechanism, has significant effects on the regulation of osteoblast function, such as osteoblast differentiation, proliferation, and apoptosis. Osteoblasts, which play an important role in maintaining bone homeostasis, have attracted increasing attention in recent years. Up till now, Several signaling pathways have been proved to regulate autophagy of osteoblasts, including the AMPK, NF-κB, FoxO3 and other signaling pathways. This article reviews the recent progress in understanding osteoblast autophagy and mitophagy in the context of periprosthetic osteolysis and the signaling pathways which are involved in these processes. By summarizing previous studies describing the mechanism underlying osteoblast autophagy, we wish to contribute new therapeutic ideas and potential therapeutic targets for periprosthetic osteolysis.","PeriodicalId":73072,"journal":{"name":"Frontiers in cell death","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139864238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-05DOI: 10.3389/fceld.2024.1337724
YingChu Gu, ZeRui Wu, Heng Xie, Tao Fang, Qiufei Wang, Ye Gu
Periprosthetic osteolysis is a difficult-to-treat complication of arthroplasty. The pathological mechanisms of periprosthetic osteolysis are mainly weakened function of osteoblasts and excessive activation of osteoclasts. Many studies have demonstrated that the imbalance between the formation of bone by osteoblasts and the absorption of bone by osteoclasts is the direct cause of osteolytic diseases. Autophagy, as an important self-protective cellular mechanism, has significant effects on the regulation of osteoblast function, such as osteoblast differentiation, proliferation, and apoptosis. Osteoblasts, which play an important role in maintaining bone homeostasis, have attracted increasing attention in recent years. Up till now, Several signaling pathways have been proved to regulate autophagy of osteoblasts, including the AMPK, NF-κB, FoxO3 and other signaling pathways. This article reviews the recent progress in understanding osteoblast autophagy and mitophagy in the context of periprosthetic osteolysis and the signaling pathways which are involved in these processes. By summarizing previous studies describing the mechanism underlying osteoblast autophagy, we wish to contribute new therapeutic ideas and potential therapeutic targets for periprosthetic osteolysis.
{"title":"Regulatory signaling pathways of osteoblast autophagy in periprosthetic osteolysis","authors":"YingChu Gu, ZeRui Wu, Heng Xie, Tao Fang, Qiufei Wang, Ye Gu","doi":"10.3389/fceld.2024.1337724","DOIUrl":"https://doi.org/10.3389/fceld.2024.1337724","url":null,"abstract":"Periprosthetic osteolysis is a difficult-to-treat complication of arthroplasty. The pathological mechanisms of periprosthetic osteolysis are mainly weakened function of osteoblasts and excessive activation of osteoclasts. Many studies have demonstrated that the imbalance between the formation of bone by osteoblasts and the absorption of bone by osteoclasts is the direct cause of osteolytic diseases. Autophagy, as an important self-protective cellular mechanism, has significant effects on the regulation of osteoblast function, such as osteoblast differentiation, proliferation, and apoptosis. Osteoblasts, which play an important role in maintaining bone homeostasis, have attracted increasing attention in recent years. Up till now, Several signaling pathways have been proved to regulate autophagy of osteoblasts, including the AMPK, NF-κB, FoxO3 and other signaling pathways. This article reviews the recent progress in understanding osteoblast autophagy and mitophagy in the context of periprosthetic osteolysis and the signaling pathways which are involved in these processes. By summarizing previous studies describing the mechanism underlying osteoblast autophagy, we wish to contribute new therapeutic ideas and potential therapeutic targets for periprosthetic osteolysis.","PeriodicalId":73072,"journal":{"name":"Frontiers in cell death","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139804576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-29DOI: 10.3389/fceld.2023.1322780
Francisca Magum Timothy, T. Zininga
Plasmodium falciparum, the predominant cause of severe malaria, thrives within both poikilotherm mosquitoes and homeotherm humans, navigating challenging temperature shifts during its life cycle. Survival in such varying environments necessitate the development of robust mechanisms, including a sophisticated protein folding system to mitigate proteopathy. The parasite needs to control the survival of its host cells which affects its chances of development and propagation. Central to this system are heat shock proteins (Hsps), among which small Hsps (sHsps) play pivotal roles in maintaining proteostasis (protein homeostasis). In both humans and P. falciparum, numerous sHsps have been identified, making them attractive candidates as biomarkers for diagnostic and drug development strategies. Evidence is accumulating suggesting that these sHsps participate in cell death processes, potentially influencing disease pathogenesis. Despite their significance, the precise functions of sHsps in P. falciparum’s adaptation to stress conditions remains largely unknown. Comparative structural analysis of sHsps between human and P. falciparum reveals species-specific variations. Despite conserved tertiary structures, unique motifs are found in parasite sHsps which may modulate specialised chaperone functions. This review discusses the conserved and distinctive motifs of sHsps from the human host and the parasite, offering insights into shared and unique attributes. These findings illuminate the potential for species-specific targeting of sHsps, as players in cell death processes that may foster innovative biomarker identification approaches. As malaria continues to ravage Sub-Saharan Africa, understanding the molecular intricacies guiding parasite survival are essential in the development of interventions with heightened efficacy against this global health crisis.
{"title":"Small heat shock proteins as modulators of cell death in Plasmodium falciparum parasites and its human host","authors":"Francisca Magum Timothy, T. Zininga","doi":"10.3389/fceld.2023.1322780","DOIUrl":"https://doi.org/10.3389/fceld.2023.1322780","url":null,"abstract":"Plasmodium falciparum, the predominant cause of severe malaria, thrives within both poikilotherm mosquitoes and homeotherm humans, navigating challenging temperature shifts during its life cycle. Survival in such varying environments necessitate the development of robust mechanisms, including a sophisticated protein folding system to mitigate proteopathy. The parasite needs to control the survival of its host cells which affects its chances of development and propagation. Central to this system are heat shock proteins (Hsps), among which small Hsps (sHsps) play pivotal roles in maintaining proteostasis (protein homeostasis). In both humans and P. falciparum, numerous sHsps have been identified, making them attractive candidates as biomarkers for diagnostic and drug development strategies. Evidence is accumulating suggesting that these sHsps participate in cell death processes, potentially influencing disease pathogenesis. Despite their significance, the precise functions of sHsps in P. falciparum’s adaptation to stress conditions remains largely unknown. Comparative structural analysis of sHsps between human and P. falciparum reveals species-specific variations. Despite conserved tertiary structures, unique motifs are found in parasite sHsps which may modulate specialised chaperone functions. This review discusses the conserved and distinctive motifs of sHsps from the human host and the parasite, offering insights into shared and unique attributes. These findings illuminate the potential for species-specific targeting of sHsps, as players in cell death processes that may foster innovative biomarker identification approaches. As malaria continues to ravage Sub-Saharan Africa, understanding the molecular intricacies guiding parasite survival are essential in the development of interventions with heightened efficacy against this global health crisis.","PeriodicalId":73072,"journal":{"name":"Frontiers in cell death","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139209681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-14DOI: 10.3389/fceld.2023.1182239
Bjarne Goebel, Laura Carpanedo, Susanne Reif, Tamara Göbel, Svenja Simonyi, Nils Helge Schebb, Dieter Steinhilber, Ann-Kathrin Häfner
Since 2005, the original three cell death mechanisms apoptosis, autophagy and necrosis are accompanied by several new forms. The most recent member, ferroptosis, was first described in 2012 and is characterized by the accumulation of iron and increased lipid peroxidation. In this study, we present a model system to study ferroptotic states in stably transfected HEK293T cells, using acyl-CoA synthetase long chain family member 4 (ACSL4), a biomarker of ferroptosis, and/or lysophosphatidylcholine acyltransferase 2 (LPCAT2), a transferase responsible for the lipid remodeling process. In addition, we introduced an inducible expression system for 5-lipoxygenase (LO), 15-LO1 and 15-LO2, to trigger enzymatic lipid peroxidation. We characterized the system in terms of ACSL4, LPCAT2 and LO expression both on Western blot level and by laser scanning confocal microscopy as well as the intracellular localization of all enzymes. Furthermore, we verified inducibility and activity of our LOs and, in addition, analyzed non-esterified (free) and total amounts of oxylipins. When cells were incubated with the ferroptosis-inducing agents GPX4 inhibitor RSL3 or GSH reducing erastin, we observed a decrease in cell viability that was strongly enhanced in the presence of ACSL4 and LPCAT2. Interestingly, additional expression of LPCAT2 resulted in altered localization of 15-LO1, which shifted from the cytosol to the nuclear membrane. A similar localization occurred after treatment with RSL3. Therefore, on one hand, we propose that LPCAT2 is an acyltransferase that promotes ferroptotic conditions, and on the other hand, we introduce a new cell-based model system suitable for studying ferroptosis.
{"title":"Development of a cell-based model system for the investigation of ferroptosis","authors":"Bjarne Goebel, Laura Carpanedo, Susanne Reif, Tamara Göbel, Svenja Simonyi, Nils Helge Schebb, Dieter Steinhilber, Ann-Kathrin Häfner","doi":"10.3389/fceld.2023.1182239","DOIUrl":"https://doi.org/10.3389/fceld.2023.1182239","url":null,"abstract":"Since 2005, the original three cell death mechanisms apoptosis, autophagy and necrosis are accompanied by several new forms. The most recent member, ferroptosis, was first described in 2012 and is characterized by the accumulation of iron and increased lipid peroxidation. In this study, we present a model system to study ferroptotic states in stably transfected HEK293T cells, using acyl-CoA synthetase long chain family member 4 (ACSL4), a biomarker of ferroptosis, and/or lysophosphatidylcholine acyltransferase 2 (LPCAT2), a transferase responsible for the lipid remodeling process. In addition, we introduced an inducible expression system for 5-lipoxygenase (LO), 15-LO1 and 15-LO2, to trigger enzymatic lipid peroxidation. We characterized the system in terms of ACSL4, LPCAT2 and LO expression both on Western blot level and by laser scanning confocal microscopy as well as the intracellular localization of all enzymes. Furthermore, we verified inducibility and activity of our LOs and, in addition, analyzed non-esterified (free) and total amounts of oxylipins. When cells were incubated with the ferroptosis-inducing agents GPX4 inhibitor RSL3 or GSH reducing erastin, we observed a decrease in cell viability that was strongly enhanced in the presence of ACSL4 and LPCAT2. Interestingly, additional expression of LPCAT2 resulted in altered localization of 15-LO1, which shifted from the cytosol to the nuclear membrane. A similar localization occurred after treatment with RSL3. Therefore, on one hand, we propose that LPCAT2 is an acyltransferase that promotes ferroptotic conditions, and on the other hand, we introduce a new cell-based model system suitable for studying ferroptosis.","PeriodicalId":73072,"journal":{"name":"Frontiers in cell death","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134901714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-30DOI: 10.3389/fceld.2023.1281137
Katherine P. Lee, Benjamin Epstein, Camille M. Lake, Andrew L. Snow
For effective adaptive immunity, T lymphocytes must rapidly expand and contract in an antigen-specific manner to effectively control invading pathogens and preserve immunological memory, without sustaining excessive collateral damage to host tissues. Starting from initial antigen encounter, carefully calibrated programmed cell death pathways are critical for maintaining homeostasis over distinct phases of the T cell response. Restimulation-induced cell death (RICD), a self-regulatory apoptosis pathway triggered by re-engagement of the T cell receptor (TCR), is particularly important for constraining effector T cell expansion to preclude overt immunopathology; indeed, genetic disorders affecting key molecules involved in RICD execution can manifest in excessive lymphoproliferation, malignancy, and autoimmunity. Herein we review our current knowledge of how RICD sensitivity is ultimately regulated over the course of an immune response, including recent revelations on molecules that tune RICD by enforcing resistance or promoting susceptibility in expanding versus mature effector T cells, respectively. Detailed dissection of the molecular and temporal control of RICD also illuminates novel therapeutic strategies for correcting abnormal T cell responses noted in various immune disorders by ultimately tuning RICD sensitivity.
{"title":"Molecular and temporal control of restimulation-induced cell death (RICD) in T lymphocytes","authors":"Katherine P. Lee, Benjamin Epstein, Camille M. Lake, Andrew L. Snow","doi":"10.3389/fceld.2023.1281137","DOIUrl":"https://doi.org/10.3389/fceld.2023.1281137","url":null,"abstract":"For effective adaptive immunity, T lymphocytes must rapidly expand and contract in an antigen-specific manner to effectively control invading pathogens and preserve immunological memory, without sustaining excessive collateral damage to host tissues. Starting from initial antigen encounter, carefully calibrated programmed cell death pathways are critical for maintaining homeostasis over distinct phases of the T cell response. Restimulation-induced cell death (RICD), a self-regulatory apoptosis pathway triggered by re-engagement of the T cell receptor (TCR), is particularly important for constraining effector T cell expansion to preclude overt immunopathology; indeed, genetic disorders affecting key molecules involved in RICD execution can manifest in excessive lymphoproliferation, malignancy, and autoimmunity. Herein we review our current knowledge of how RICD sensitivity is ultimately regulated over the course of an immune response, including recent revelations on molecules that tune RICD by enforcing resistance or promoting susceptibility in expanding versus mature effector T cells, respectively. Detailed dissection of the molecular and temporal control of RICD also illuminates novel therapeutic strategies for correcting abnormal T cell responses noted in various immune disorders by ultimately tuning RICD sensitivity.","PeriodicalId":73072,"journal":{"name":"Frontiers in cell death","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136102801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-08-29DOI: 10.3389/fceld.2023.1219672
Géraldine Cuvelier, Perrine Vermonden, J. Rousseau, O. Féron, R. Rezsohazy, Y. Larondelle
In contrast to canonical ferroptosis inducers, highly peroxidable conjugated linolenic acids (CLnA) directly fuel the lipid peroxidation cascade upon their incorporation into membrane phospholipids. Little is known, however, about the cytotoxicity level of CLnAs to normal epithelial cells. Caco-2 cells, derived from colorectal adenocarcinoma, spontaneously differentiate into enterocyte-like cells over a period of 21 days of cell culturing, allowing for graduated phenotypic shift from proliferative, undifferentiated cells to a functional intestinal barrier. We exploited this property to assess the sensitivity of Caco-2 cells to CLnAs at different stages of differentiation. Our results show a significant decrease in CLnA-induced ferroptotic cell death over time. The acquired resistance aligned with decreases in cell proliferation and in the extent of lipid peroxidation, as well as with an increase in the expression of GPX4 upon differentiation. These results highlight that while CLnAs are highly toxic for proliferating cancer cells, differentiated epithelial cells are resistant to CLnA-induced ferroptosis. Therefore, this study gives credential to the therapeutic use of CLnAs as an anticancer strategy and offers a new model study to further investigate the safety of peroxidable fatty acids in differentiated cells.
{"title":"Resistance to CLnA-induced ferroptosis is acquired in Caco-2 cells upon differentiation","authors":"Géraldine Cuvelier, Perrine Vermonden, J. Rousseau, O. Féron, R. Rezsohazy, Y. Larondelle","doi":"10.3389/fceld.2023.1219672","DOIUrl":"https://doi.org/10.3389/fceld.2023.1219672","url":null,"abstract":"In contrast to canonical ferroptosis inducers, highly peroxidable conjugated linolenic acids (CLnA) directly fuel the lipid peroxidation cascade upon their incorporation into membrane phospholipids. Little is known, however, about the cytotoxicity level of CLnAs to normal epithelial cells. Caco-2 cells, derived from colorectal adenocarcinoma, spontaneously differentiate into enterocyte-like cells over a period of 21 days of cell culturing, allowing for graduated phenotypic shift from proliferative, undifferentiated cells to a functional intestinal barrier. We exploited this property to assess the sensitivity of Caco-2 cells to CLnAs at different stages of differentiation. Our results show a significant decrease in CLnA-induced ferroptotic cell death over time. The acquired resistance aligned with decreases in cell proliferation and in the extent of lipid peroxidation, as well as with an increase in the expression of GPX4 upon differentiation. These results highlight that while CLnAs are highly toxic for proliferating cancer cells, differentiated epithelial cells are resistant to CLnA-induced ferroptosis. Therefore, this study gives credential to the therapeutic use of CLnAs as an anticancer strategy and offers a new model study to further investigate the safety of peroxidable fatty acids in differentiated cells.","PeriodicalId":73072,"journal":{"name":"Frontiers in cell death","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91081004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-06-20DOI: 10.3389/fceld.2023.1209641
Sanjay Saini, Edward Owusu-Ansah
Ferroptosis is a specific form of non-apoptotic cell death that is driven by iron-dependent phospholipid peroxidation. Research over the past decade has contributed to our understanding of how this important cell death process is regulated in mammalian systems, especially with regard to the distinct modes of induction, the role of metabolic signals, the organelles involved, implications of ferroptosis for development and aging, and how our improved understanding of the process can be exploited for therapeutic purposes. Other studies have described variants of this ancient cell death process in cyanobacteria, plants and protozoans. Emerging evidence indicates that a ferroptosis-like form of cell death exists in fruit flies (Drosophila melanogaster). Due to the extensive homology of genes in Drosophila melanogaster and Drosophila suzukii, unique aspects of ferroptosis in Drosophila melanogaster may be of particular relevance for developing targeted pesticides against Drosophila suzukii—a major invasive agricultural pest of the berry and wine industry in Southeast Asia, Europe and America. Further, aspects of ferroptosis in Drosophila melanogaster that are conserved in insects in general may provide the basis for identifying new insecticides for controlling the spread of vector-borne diseases such as malaria. In this perspective, we highlight some of the studies in Drosophila melanogaster that have sought to improve our understanding of the ferroptosis-like form of cell death that operates in this organism and conclude with a discussion of the opportunities and challenges for studying this phenomenon in fruit flies.
{"title":"Dissecting the mechanism of regulation of a ferroptosis-like form of cell death in Drosophila melanogaster","authors":"Sanjay Saini, Edward Owusu-Ansah","doi":"10.3389/fceld.2023.1209641","DOIUrl":"https://doi.org/10.3389/fceld.2023.1209641","url":null,"abstract":"Ferroptosis is a specific form of non-apoptotic cell death that is driven by iron-dependent phospholipid peroxidation. Research over the past decade has contributed to our understanding of how this important cell death process is regulated in mammalian systems, especially with regard to the distinct modes of induction, the role of metabolic signals, the organelles involved, implications of ferroptosis for development and aging, and how our improved understanding of the process can be exploited for therapeutic purposes. Other studies have described variants of this ancient cell death process in cyanobacteria, plants and protozoans. Emerging evidence indicates that a ferroptosis-like form of cell death exists in fruit flies (Drosophila melanogaster). Due to the extensive homology of genes in Drosophila melanogaster and Drosophila suzukii, unique aspects of ferroptosis in Drosophila melanogaster may be of particular relevance for developing targeted pesticides against Drosophila suzukii—a major invasive agricultural pest of the berry and wine industry in Southeast Asia, Europe and America. Further, aspects of ferroptosis in Drosophila melanogaster that are conserved in insects in general may provide the basis for identifying new insecticides for controlling the spread of vector-borne diseases such as malaria. In this perspective, we highlight some of the studies in Drosophila melanogaster that have sought to improve our understanding of the ferroptosis-like form of cell death that operates in this organism and conclude with a discussion of the opportunities and challenges for studying this phenomenon in fruit flies.","PeriodicalId":73072,"journal":{"name":"Frontiers in cell death","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76954015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-06-16DOI: 10.3389/fceld.2023.1197400
R. Lockshin
The concept of biological cell death—that is, cell death that is neither accidental nor chaotic—has existed and has been obvious since at least the beginning of the 20th C, but it was noticed by other than specialists apt choices of words that caught the spirit of the time, “programmed cell death” and “apoptosis” caught the attention of a wider range of scientists. Then, by the early 1990s the recognition of at least two genes that were important to cancer and other diseases by controlling cell death (p53, Bcl-2, and Fas); recognition that cell death could be controlled by a highly conserved family of proteases; and the development of rapid and easy means of measuring cell death, led to the explosion of the field as a subject of research. Today we recognize many variations on the theme of biological cell death, but many mysteries remain. The most important of these remaining mysteries is that we recognize many of the penultimate and ultimate steps to kill cells, but it is rarely clear how and why these steps are activated. Most likely they are activated by an interaction of several metabolic steps, but we will need more high-powered analysis to determine how this interaction functions.
{"title":"One-half century (or more) of study of cell death: origins, present, and perhaps future","authors":"R. Lockshin","doi":"10.3389/fceld.2023.1197400","DOIUrl":"https://doi.org/10.3389/fceld.2023.1197400","url":null,"abstract":"The concept of biological cell death—that is, cell death that is neither accidental nor chaotic—has existed and has been obvious since at least the beginning of the 20th C, but it was noticed by other than specialists apt choices of words that caught the spirit of the time, “programmed cell death” and “apoptosis” caught the attention of a wider range of scientists. Then, by the early 1990s the recognition of at least two genes that were important to cancer and other diseases by controlling cell death (p53, Bcl-2, and Fas); recognition that cell death could be controlled by a highly conserved family of proteases; and the development of rapid and easy means of measuring cell death, led to the explosion of the field as a subject of research. Today we recognize many variations on the theme of biological cell death, but many mysteries remain. The most important of these remaining mysteries is that we recognize many of the penultimate and ultimate steps to kill cells, but it is rarely clear how and why these steps are activated. Most likely they are activated by an interaction of several metabolic steps, but we will need more high-powered analysis to determine how this interaction functions.","PeriodicalId":73072,"journal":{"name":"Frontiers in cell death","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72557402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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