scholarly journals Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses

2016 ◽  
Vol 113 (44) ◽  
pp. E6806-E6812 ◽  
Author(s):  
Yang Ou ◽  
Shang-Jui Wang ◽  
Dawei Li ◽  
Bo Chu ◽  
Wei Gu
Keyword(s):  
Cell Death ◽  
Metabolic Pathways ◽  
Cell Metabolism ◽  
Specific Inhibitor ◽  
Polyamine Metabolism ◽  
Cycle Arrest ◽  
Induced Stress ◽  
Rate Limiting ◽  
Insight Into

Although p53-mediated cell-cycle arrest, senescence, and apoptosis remain critical barriers to cancer development, the emerging role of p53 in cell metabolism, oxidative responses, and ferroptotic cell death has been a topic of great interest. Nevertheless, it is unclear how p53 orchestrates its activities in multiple metabolic pathways into tumor suppressive effects. Here, we identified the SAT1 (spermidine/spermine N1-acetyltransferase 1) gene as a transcription target of p53. SAT1 is a rate-limiting enzyme in polyamine catabolism critically involved in the conversion of spermidine and spermine back to putrescine. Surprisingly, we found that activation of SAT1 expression induces lipid peroxidation and sensitizes cells to undergo ferroptosis upon reactive oxygen species (ROS)-induced stress, which also leads to suppression of tumor growth in xenograft tumor models. Notably, SAT1 expression is down-regulated in human tumors, and CRISPR-cas9–mediated knockout of SAT1 expression partially abrogates p53-mediated ferroptosis. Moreover, SAT1 induction is correlated with the expression levels of arachidonate 15-lipoxygenase (ALOX15), and SAT1-induced ferroptosis is significantly abrogated in the presence of PD146176, a specific inhibitor of ALOX15. Thus, our findings uncover a metabolic target of p53 involved in ferroptotic cell death and provide insight into the regulation of polyamine metabolism and ferroptosis-mediated tumor suppression.

MicroRNA-1225-5p acts as a tumor-suppressor in laryngeal cancer via targeting CDC14B

2019 ◽  
Vol 400 (2) ◽  
pp. 237-246 ◽  
Author(s):  
Peng Sun ◽  
Dan Zhang ◽  
Haiping Huang ◽  
Yafeng Yu ◽  
Zhendong Yang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Division ◽  
Cell Cycle Arrest ◽  
Molecular Mechanisms ◽  
Normal Tissues ◽  
Cycle Arrest ◽  
Enhanced Expression ◽  
Insight Into

Abstract This study aimed to investigate the role of miRNA-1225-5p (miR-1225) in laryngeal carcinoma (LC). We found that the expression of miR-1225 was suppressed in human LC samples, while CDC14B (cell division cycle 14B) expression was reinforced in comparison with surrounding normal tissues. We also demonstrated that enhanced expression of miR-1225 impaired the proliferation and survival of LC cells, and resulted in G1/S cell cycle arrest. In contrast, reduced expression of miR-1225 promoted cell survival. Moreover, miR-1225 resulted in G1/S cell cycle arrest and enhanced cell death. Further, miR-1225 targets CDC14B 3′-UTR and recovery of CDC14B expression counteracted the suppressive influence of miR-1225 on LC cells. Thus, these findings offer insight into the biological and molecular mechanisms behind the development of LC.

scholarly journals The Potential Role of Changes in the Glucose and Lipid Metabolic Pathways in Gastrointestinal Cancer Progression: Strategy in Cancer Therapy

2021 ◽  
pp. 1-8
Author(s):  
Gordon A. Ferns ◽  
Milad Shahini Shams Abadi ◽  
Ahmad Raeisi ◽  
Mohammad-Hassan Arjmand
Keyword(s):  
Cancer Progression ◽  
Metabolic Pathways ◽  
Cell Metabolism ◽  
Tumor Formation ◽  
High Rate ◽  
Metabolic Inhibitors ◽  
Chemotherapy Drugs ◽  
Poor Outcomes ◽  
Rate Limiting

<b><i>Background:</i></b> Changes in cell metabolism are a well-known feature of some cancers, and this may be involved in the etiology of tumor formation and progression, as well as tumor heterogeneity. These changes may affect fatty acid metabolism and glycolysis and are required to provide the increase in energy necessary for the high rate of proliferation of cancer cells. Gastrointestinal cancers remain a difficult-to-treat cancer, particularly as they are usually diagnosed at a late stage of disease and are associated with poor outcomes. <b><i>Summary:</i></b> Recently, the changes in the metabolic pathways, including the expression of the rate-limiting enzymes involved, have been considered to be a potential target for therapy for gastrointestinal tumors. <b><i>Key Message:</i></b> A combination of routine chemotherapy drugs with metabolic inhibitors may improve the effectiveness of treatment.

scholarly journals Salicylic Acid Accumulation Controlled by LSD1 Is Essential in Triggering Cell Death in Response to Abiotic Stress

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 962
Author(s):  
Maciej Jerzy Bernacki ◽  
Anna Rusaczonek ◽  
Weronika Czarnocka ◽  
Stanisław Karpiński
Keyword(s):  
Cell Death ◽  
Salicylic Acid ◽  
Abiotic Stress ◽  
Wild Type ◽  
Pr Genes ◽  
Genes Expression ◽  
Salicylic Acid Accumulation ◽  
Cell Death Phenotype ◽  
Insight Into

Salicylic acid (SA) is well known hormonal molecule involved in cell death regulation. In response to a broad range of environmental factors (e.g., high light, UV, pathogens attack), plants accumulate SA, which participates in cell death induction and spread in some foliar cells. LESION SIMULATING DISEASE 1 (LSD1) is one of the best-known cell death regulators in Arabidopsis thaliana. The lsd1 mutant, lacking functional LSD1 protein, accumulates SA and is conditionally susceptible to many biotic and abiotic stresses. In order to get more insight into the role of LSD1-dependent regulation of SA accumulation during cell death, we crossed the lsd1 with the sid2 mutant, caring mutation in ISOCHORISMATE SYNTHASE 1(ICS1) gene and having deregulated SA synthesis, and with plants expressing the bacterial nahG gene and thus decomposing SA to catechol. In response to UV A+B irradiation, the lsd1 mutant exhibited clear cell death phenotype, which was reversed in lsd1/sid2 and lsd1/NahG plants. The expression of PR-genes and the H2O2 content in UV-treated lsd1 were significantly higher when compared with the wild type. In contrast, lsd1/sid2 and lsd1/NahG plants demonstrated comparability with the wild-type level of PR-genes expression and H2O2. Our results demonstrate that SA accumulation is crucial for triggering cell death in lsd1, while the reduction of excessive SA accumulation may lead to a greater tolerance toward abiotic stress.

scholarly journals The Role of Cell Metabolism in Innate Immune Memory

2020 ◽  
pp. 1-9
Author(s):  
Anaisa Valido Ferreira ◽  
Jorge Domiguéz-Andrés ◽  
Mihai Gheorghe Netea
Keyword(s):  
Metabolic Pathways ◽  
Tricarboxylic Acid Cycle ◽  
Cell Metabolism ◽  
Innate Immune ◽  
Immune Memory ◽  
Functional Changes ◽  
Trained Immunity ◽  
Health And Disease

Immunological memory is classically attributed to adaptive immune responses, but recent studies have shown that challenged innate immune cells can display long-term functional changes that increase nonspecific responsiveness to subsequent infections. This phenomenon, coined <i>trained immunity</i> or <i>innate immune memory</i>, is based on the epigenetic reprogramming and the rewiring of intracellular metabolic pathways. Here, we review the different metabolic pathways that are modulated in trained immunity. Glycolysis, oxidative phosphorylation, the tricarboxylic acid cycle, amino acid, and lipid metabolism are interplaying pathways that are crucial for the establishment of innate immune memory. Unraveling this metabolic wiring allows for a better understanding of innate immune contribution to health and disease. These insights may open avenues for the development of future therapies that aim to harness or dampen the power of the innate immune response.

scholarly journals Deficiency of VCP-Interacting Membrane Selenoprotein (VIMP) Leads to G1 Cell Cycle Arrest and Cell Death in MIN6 Insulinoma Cells

2018 ◽  
Vol 51 (5) ◽  
pp. 2185-2197 ◽  
Author(s):  
Lili Men ◽  
Juan Sun ◽  
Decheng Ren
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Insulin Secretion ◽  
Cell Apoptosis ◽  
Β Cells ◽  
Β Cell ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
Insulinoma Cells

Background/Aims: VCP-interacting membrane selenoprotein (VIMP), an ER resident selenoprotein, is highly expressed in β-cells, however, the role of VIMP in β-cells has not been characterized. In this study, we studied the relationship between VIMP deficiency and β-cell survival in MIN6 insulinoma cells. Methods: To determine the role of VIMP in β-cells, lentiviral VIMP shRNAs were used to knock down (KD) expression of VIMP in MIN6 cells. Cell death was quantified by propidium iodide (PI) staining followed by flow cytometric analyses using a FACS Caliber and FlowJo software. Cell apoptosis and proliferation were determined by TUNEL assay and Ki67 staining, respectively. Cell cycle was analyzed after PI staining. Results: The results show that 1) VIMP suppression induces β-cell apoptosis, which is associated with a decrease in Bcl-xL, and the β-cell apoptosis induced by VIMP suppression can be inhibited by overexpression of Bcl-xL; 2) VIMP knockdown (KD) decreases cell proliferation and G1 cell cycle arrest by accumulating p27 and decreasing E2F1; 3) VIMP KD suppresses unfolded protein response (UPR) activation by regulating the IRE1α and PERK pathways; 4) VIMP KD increases insulin secretion. Conclusion: These results suggest that VIMP may function as a novel regulator to modulate β-cell survival, proliferation, cell cycle, UPR and insulin secretion in MIN6 cells.

scholarly journals IMiDs prime myeloma cells for daratumumab-mediated cytotoxicity through loss of Ikaros and Aiolos

Blood ◽  
2018 ◽  
Vol 132 (20) ◽  
pp. 2166-2178 ◽  
Author(s):  
Pasquale L. Fedele ◽  
Simon N. Willis ◽  
Yang Liao ◽  
Michael S. Low ◽  
Jai Rautela ◽  
...  
Keyword(s):  
Cell Death ◽  
Regulatory Networks ◽  
Nk Cell ◽  
Surface Expression ◽  
Nucleosome Remodeling ◽  
Interferon Stimulated Genes ◽  
Cd38 Expression ◽  
Cycle Arrest ◽  
Transcriptional Changes ◽  
Insight Into

Abstract Recent studies have demonstrated that the immunomodulatory drugs (IMiDs) lead to the degradation of the transcription factors Ikaros and Aiolos. However, why their loss subsequently leads to multiple myeloma (MM) cell death remains unclear. Using CRISPR-Cas9 genome editing, we have deleted IKZF1/Ikaros and IKZF3/Aiolos in human MM cell lines to gain further insight into their downstream gene regulatory networks. Inactivation of either factor alone recapitulates the cell intrinsic action of the IMiDs, resulting in cell cycle arrest and induction of apoptosis. Furthermore, evaluation of the transcriptional changes resulting from their loss demonstrates striking overlap with lenalidomide treatment. This was not dependent on reduction of the IRF4-MYC “axis,” as neither protein was consistently downregulated, despite cell death occurring, and overexpression of either factor failed to rescue for Ikaros loss. Importantly, Ikaros and Aiolos repress the expression of interferon-stimulated genes (ISGs), including CD38, and their loss led to the activation of an interferon-like response, contributing to MM cell death. Ikaros/Aiolos repressed CD38 expression through interaction with the nucleosome remodeling and deacetylase complex in MM. IMiD-induced loss of Ikaros or treatment with interferon resulted in an upregulation of CD38 surface expression on MM cells, priming for daratumumab-induced NK cell-mediated antibody-dependent cellular cytotoxicity. These results give further insight into the mechanism of action of the IMiDs and provide mechanistic rationale for combination with anti-CD38 monoclonal antibodies.

scholarly journals cAMP metabolism controls caspase-11 inflammasome activation and pyroptosis in sepsis

2019 ◽  
Vol 5 (5) ◽  
pp. eaav5562 ◽  
Author(s):  
Ruochan Chen ◽  
Ling Zeng ◽  
Shan Zhu ◽  
Jiao Liu ◽  
Herbert J. Zeh ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Inflammatory Responses ◽  
Poly I:C ◽  
Inflammasome Activation ◽  
Proof Of Concept ◽  
Potential Therapeutic Target ◽  
Camp Metabolism ◽  
Camp Hydrolysis ◽  
Insight Into

The ability of cytosolic lipopolysaccharide (LPS) to activate caspase-11–dependent nonclassical inflammasome is intricately controlled to avoid excessive inflammatory responses. However, very little is known about the regulatory role of various metabolic pathways in the control of caspase-11 activation. Here, we demonstrate that l-adrenaline can act on receptor ADRA2B to inhibit the activation of the caspase-11 inflammasome by cytosolic LPS or Escherichia coli infection in macrophages. l-adrenaline–induced cAMP production via the enzyme ADCY4 promotes protein kinase A (PKA) activation, which then blocks the caspase-11–mediated proteolytic maturation of interleukin-1β, gasdermin D (GSDMD) cleavage, and consequent DAMP release. Inhibition of PDE8A-mediated cAMP hydrolysis limits caspase-11 inflammasome activation and pyroptosis in macrophages. Consequently, pharmacological modulation of the ADRA2B-ADCY4-PDE8A-PKA axis, knockout of caspase-11 (Casp11−/−), or Gsdmd inactivation (GsdmdI105N/I105N) similarly protects against LPS-induced lethality in poly(I:C)-primed mice. Our results provide previously unidentified mechanistic insight into immune regulation by cAMP and represent a proof of concept that immunometabolism constitutes a potential therapeutic target in sepsis.

scholarly journals Role of two metacaspases in development and pathogenicity of the Rice Blast fungus, Magnaporthe oryzae

2020 ◽  
Author(s):  
Jessie Fernandez ◽  
Victor Lopez ◽  
Lisa Kinch ◽  
Mariel A. Pfeifer ◽  
Hillery Gray ◽  
...  
Keyword(s):  
Cell Death ◽  
Food Security ◽  
Life Cycle ◽  
Magnaporthe Oryzae ◽  
Rice Blast ◽  
Rice Blast Disease ◽  
Blast Disease ◽  
Complex Life Cycle ◽  
Insight Into

ABSTRACTRice blast disease caused by Magnaporthe oryzae is a devastating disease of cultivated rice worldwide. Infections by this fungus lead to a significant reduction in rice yields and threats to food security. To gain better insight into growth and cell death in M. oryzae during infection, we characterized two predicted M. oryzae metacaspase proteins, MoMca1 and MoMca2. These proteins appear to be functionally redundant and are able to complement the yeast Yca1 homologue. Biochemical analysis revealed that M. oryzae metacaspases exhibited Ca2+ dependent caspase activity in vitro. Deletion of both MoMca1 and MoMca2 in M. oryzae resulted in reduced sporulation, delay in conidial germination and attenuation of disease severity. In addition, the double ΔMomca1mca2 mutant strain showed increased radial growth in the presence of oxidative stress. Interestingly, the ΔMomca1mca2 strain showed an increase accumulation of insoluble aggregates compared to the wild-type strain during vegetative growth. Our findings suggest that MoMca1 and MoMca2 promote the clearance of insoluble aggregates in M. oryzae, demonstrating the important role these metacaspases have in fungal protein homeostasis. Furthermore, these metacaspase proteins may play additional roles, like in regulating stress responses, that would help maintain the fitness of fungal cells required for host infection.IMPORTANCEMagnaporthe oryzae causes rice blast disease that threatens global food security by resulting in the severe loss of rice production every year. A tightly regulated life cycle allows M. oryzae to disarm the host plant immune system during its biotrophic stage before triggering plant cell death in its necrotrophic stage. The ways M. oryzae navigates its complex life cycle remains unclear. This work characterizes two metacaspase proteins with peptidase activity in M. oryzae that are shown to be involved in the regulation of fungal growth and development prior to infection by potentially helping maintain fungal fitness. This study provides new insight into the role of metacaspase proteins in filamentous fungi by illustrating the delays in M. oryzae morphogenesis in the absence of these proteins. Understanding the mechanisms by which M. oryzae morphology and development promote its devastating pathogenicity may lead to the emergence of proper methods for disease control.

scholarly journals Insight into the Double-Edged Role of Ferroptosis in Disease

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1790
Author(s):  
Lei Zhang ◽  
Ruohan Jia ◽  
Huizhen Li ◽  
Huarun Yu ◽  
Keke Ren ◽  
...  
Keyword(s):  
Cell Death ◽  
Digestive System ◽  
Kidney Injury ◽  
Oxygen Species ◽  
Disease Treatment ◽  
The Relationship ◽  
Insight Into ◽  
New Strategies ◽  
Research Hotspots

Ferroptosis, a newly described type of iron-dependent programmed cell death that is distinct from apoptosis, necroptosis, and other types of cell death, is involved in lipid peroxidation (LP), reactive oxygen species (ROS) production, and mitochondrial dysfunction. Accumulating evidence has highlighted vital roles for ferroptosis in multiple diseases, including acute kidney injury, cancer, hepatic fibrosis, Parkinson’s disease, and Alzheimer’s disease. Therefore, ferroptosis has become one of the research hotspots for disease treatment and attracted extensive attention in recent years. This review mainly summarizes the relationship between ferroptosis and various diseases classified by the system, including the urinary system, digestive system, respiratory system, nervous system. In addition, the role and molecular mechanism of multiple inhibitors and inducers for ferroptosis are further elucidated. A deeper understanding of the relationship between ferroptosis and multiple diseases may provide new strategies for researching diseases and drug development based on ferroptosis.

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