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Small Molecule Inhibitor Screen Reveals Calcium Channel Signaling as a Mechanistic Mediator of TcdB-Induced Necrosis.
Farrow MA, Chumber NM, Bloch SC, King M, Moton-Melancon K, Shupe J, Washington MK, Spiller BW, Lacy DB
(2020) ACS Chem Biol 15: 1212-1221
MeSH Terms: Actin Cytoskeleton, Animals, Anti-Infective Agents, Bacterial Toxins, Calcium Channel Blockers, Calcium Channels, Calcium Signaling, Clostridioides difficile, Cytokines, Dihydropyridines, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Glucosyltransferases, Humans, Kinetics, Mice, NADPH Oxidases, Necrosis, Reactive Oxygen Species, Virulence Factors
Show Abstract · Added March 24, 2020
is the leading cause of nosocomial diarrhea in the United States. The primary virulence factors are two homologous glucosyltransferase toxins, TcdA and TcdB, that inactivate host Rho-family GTPases. The glucosyltransferase activity has been linked to a "cytopathic" disruption of the actin cytoskeleton and contributes to the disruption of tight junctions and the production of pro-inflammatory cytokines. TcdB is also a potent cytotoxin that causes epithelium necrotic damage through an NADPH oxidase (NOX)-dependent mechanism. We conducted a small molecule screen to identify compounds that confer protection against TcdB-induced necrosis. We identified an enrichment of "hit compounds" with a dihydropyridine (DHP) core which led to the discovery of a key early stage calcium signal that serves as a mechanistic link between TcdB-induced NOX activation and reactive oxygen species (ROS) production. Disruption of TcdB-induced calcium signaling (with both DHP and non-DHP molecules) is sufficient to ablate ROS production and prevent subsequent necrosis in cells and in a mouse model of intoxication.
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20 MeSH Terms
Multimodal Multiplexed Immunoimaging with Nanostars to Detect Multiple Immunomarkers and Monitor Response to Immunotherapies.
Ou YC, Wen X, Johnson CA, Shae D, Ayala OD, Webb JA, Lin EC, DeLapp RC, Boyd KL, Richmond A, Mahadevan-Jansen A, Rafat M, Wilson JT, Balko JM, Tantawy MN, Vilgelm AE, Bardhan R
(2020) ACS Nano 14: 651-663
MeSH Terms: Animals, B7-H1 Antigen, Biomarkers, Tumor, Cell Line, Tumor, Disease Models, Animal, Gold, Immunotherapy, Melanoma, Metal Nanoparticles, Mice, Optical Imaging, Particle Size, Surface Properties, Tumor Necrosis Factor Receptor Superfamily, Member 9
Show Abstract · Added March 17, 2020
The overexpression of immunomarker programmed cell death protein 1 (PD-1) and engagement of PD-1 to its ligand, PD-L1, are involved in the functional impairment of cluster of differentiation 8 (CD8) T cells, contributing to cancer progression. However, heterogeneities in PD-L1 expression and variabilities in biopsy-based assays render current approaches inaccurate in predicting PD-L1 status. Therefore, PD-L1 screening alone is not predictive of patient response to treatment, which motivates us to simultaneously detect multiple immunomarkers engaged in immune modulation. Here, we have developed multimodal probes, immunoactive gold nanostars (IGNs), that accurately detect PD-L1 tumor cells and CD8 T cells simultaneously , surpassing the limitations of current immunoimaging techniques. IGNs integrate the whole-body imaging of positron emission tomography with high sensitivity and multiplexing of Raman spectroscopy, enabling the dynamic tracking of both immunomarkers. IGNs also monitor response to immunotherapies in mice treated with combinatorial PD-L1 and CD137 agonists and distinguish responders from those nonresponsive to treatment. Our results showed a multifunctional nanoscale probe with capabilities that cannot be achieved with either modality alone, allowing multiplexed immunologic tumor profiling critical for predicting early response to immunotherapies.
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14 MeSH Terms
Increased reporting of fatal hepatitis associated with immune checkpoint inhibitors.
Vozy A, De Martin E, Johnson DB, Lebrun-Vignes B, Moslehi JJ, Salem JE
(2019) Eur J Cancer 123: 112-115
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Immunological, B7-H1 Antigen, CTLA-4 Antigen, Chemical and Drug Induced Liver Injury, Child, Databases, Factual, Female, Hepatitis, Autoimmune, Humans, Ipilimumab, Male, Massive Hepatic Necrosis, Middle Aged, Neoplasms, Nivolumab, Programmed Cell Death 1 Receptor, World Health Organization, Young Adult
Added November 12, 2019
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23 MeSH Terms
Zinc intoxication induces ferroptosis in A549 human lung cells.
Palmer LD, Jordan AT, Maloney KN, Farrow MA, Gutierrez DB, Gant-Branum R, Burns WJ, Romer CE, Tsui T, Allen JL, Beavers WN, Nei YW, Sherrod SD, Lacy DB, Norris JL, McLean JA, Caprioli RM, Skaar EP
(2019) Metallomics 11: 982-993
MeSH Terms: A549 Cells, Apoptosis, Cell Survival, Ferroptosis, Genomics, Humans, Lung, NAD, Necrosis, Protein Binding, Time Factors, Zinc
Show Abstract · Added August 7, 2019
Zinc (Zn) is an essential trace metal required for all forms of life, but is toxic at high concentrations. While the toxic effects of high levels of Zn are well documented, the mechanism of cell death appears to vary based on the study and concentration of Zn. Zn has been proposed as an anti-cancer treatment against non-small cell lung cancer (NSCLC). The goal of this analysis was to determine the effects of Zn on metabolism and cell death in A549 cells. Here, high throughput multi-omics analysis identified the molecular effects of Zn intoxication on the proteome, metabolome, and transcriptome of A549 human NSCLC cells after 5 min to 24 h of Zn exposure. Multi-omics analysis combined with additional experimental evidence suggests Zn intoxication induces ferroptosis, an iron and lipid peroxidation-dependent programmed cell death, demonstrating the utility of multi-omics analysis to identify cellular response to intoxicants.
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12 MeSH Terms
Apoptosis signal-regulating kinase 1 activation by Nox1-derived oxidants is required for TNFα receptor endocytosis.
Choi H, Stark RJ, Raja BS, Dikalova A, Lamb FS
(2019) Am J Physiol Heart Circ Physiol 316: H1528-H1537
MeSH Terms: Animals, Aorta, Thoracic, Cells, Cultured, Endocytosis, MAP Kinase Kinase Kinase 5, Mice, Inbred C57BL, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, NADPH Oxidase 1, Receptors, Tumor Necrosis Factor, Type I, Signal Transduction, Superoxides, Tumor Necrosis Factor-alpha
Show Abstract · Added April 3, 2019
Tumor necrosis factor-α (TNFα) is a proinflammatory cytokine that is closely linked to the development of cardiovascular disease. TNFα activates NADPH oxidase 1 (Nox1) and reactive oxygen species (ROS), including superoxide (O), production extracellularly is required for subsequent signaling in vascular smooth muscle cells (VSMCs). Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that is activated by oxidation of associated thioredoxin. The role of ASK1 in Nox1-mediated signaling by TNFα is poorly defined. We hypothesized that ASK1 is required for TNFα receptor endocytosis and subsequent inflammatory TNFα signaling. We employed a knockdown strategy to explore the role of ASK1 in TNFα signaling in VSMCs. siRNA targeting ASK1 had no effect on TNFα-induced extracellular O production. However, siASK1 inhibited receptor endocytosis as well as phosphorylation of two endocytosis-related proteins, dynamin1 and caveolin1. Intracellular O production was subsequently reduced, as were other inflammatory signaling steps including NF-κB activation, IL-6 production, inducible nitric oxide synthase and VCAM expression, and VSMC proliferation. Prolonged exposure to TNFα (24 h) increased tumor necrosis factor receptor (TNFR) subtype 1 and 2 expression, and these effects were also attenuated by siASK1. ASK1 coimmunoprecipitated with both Nox1 and the leucine rich repeat containing 8A anion channel, two essential components of the TNFR1 signaling complex. Activation of ASK1 by autophosphorylation at Thr845 occurs following thioredoxin dissociation, and this requires the presence of Nox1. Thus, Nox1 is part of the multiprotein ASK1 signaling complex. In response to TNFα, ASK1 is activated by Nox1-derived oxidants, and this plays a critical role in translating these ROS into a physiologic response in VSMCs. Apoptosis signal-regulating kinase 1 (ASK1) drives dynamin1 and caveolin1 phosphorylation and TNFα receptor endocytosis. ASK1 modulates TNFα-induced NF-κB activation, survival, and proliferation. ASK1 and NADPH oxidase 1 (Nox1) physically associate in a multiprotein signaling complex. Nox1 is required for TNFα-induced ASK1 activation.
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13 MeSH Terms
Biophysical model-based parameters to classify tumor recurrence from radiation-induced necrosis for brain metastases.
Narasimhan S, Johnson HB, Nickles TM, Miga MI, Rana N, Attia A, Weis JA
(2019) Med Phys 46: 2487-2496
MeSH Terms: Brain Neoplasms, Humans, Magnetic Resonance Imaging, Models, Biological, Necrosis, Patient-Specific Modeling, Radiation Injuries, Radiosurgery, Recurrence, Retrospective Studies
Show Abstract · Added April 2, 2019
PURPOSE - Stereotactic radiosurgery (SRS) is used for local control treatment of patients with intracranial metastases. As a result of SRS, some patients develop radiation-induced necrosis. Radiographically, radiation-induced necrosis can appear similar to tumor recurrence in magnetic resonance (MR) T -weighted contrast-enhanced imaging, T -weighted MR imaging, and Fluid-Attenuated Inversion Recovery (FLAIR) MR imaging. Radiographic ambiguities often necessitate invasive brain biopsies to determine lesion etiology or cause delayed subsequent therapy initiation. We use a biomechanically coupled tumor growth model to estimate patient-specific model parameters and model-derived measures to noninvasively classify etiology of enhancing lesions in this patient population.
METHODS - In this initial, preliminary retrospective study, we evaluated five patients with tumor recurrence and five with radiation-induced necrosis. Longitudinal patient-specific MR imaging data were used in conjunction with the model to parameterize tumor cell proliferation rate and tumor cell diffusion coefficient, and Dice correlation coefficients were used to quantify degree of correlation between model-estimated mechanical stress fields and edema visualized from MR imaging.
RESULTS - Results found four statistically relevant parameters which can differentiate tumor recurrence and radiation-induced necrosis.
CONCLUSIONS - This preliminary investigation suggests potential of this framework to noninvasively determine the etiology of enhancing lesions in patients who previously underwent SRS for intracranial metastases.
© 2019 American Association of Physicists in Medicine.
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10 MeSH Terms
Increased Ripk1-mediated bone marrow necroptosis leads to myelodysplasia and bone marrow failure in mice.
Wagner PN, Shi Q, Salisbury-Ruf CT, Zou J, Savona MR, Fedoriw Y, Zinkel SS
(2019) Blood 133: 107-120
MeSH Terms: Animals, BH3 Interacting Domain Death Agonist Protein, Bone Marrow, Bone Marrow Diseases, Cells, Cultured, Cytokines, Hematopoietic Stem Cells, Inflammation, Mice, Mice, Inbred C57BL, Mice, Knockout, Myelodysplastic Syndromes, Necrosis, Receptor-Interacting Protein Serine-Threonine Kinases, bcl-2 Homologous Antagonist-Killer Protein
Show Abstract · Added December 11, 2018
Hematopoiesis is a dynamic system that requires balanced cell division, differentiation, and death. The 2 major modes of programmed cell death, apoptosis and necroptosis, share molecular machinery but diverge in outcome with important implications for the microenvironment; apoptotic cells are removed in an immune silent process, whereas necroptotic cells leak cellular contents that incite inflammation. Given the importance of cytokine-directed cues for hematopoietic cell survival and differentiation, the impact on hematopoietic homeostasis of biasing cell death fate to necroptosis is substantial and poorly understood. Here, we present a mouse model with increased bone marrow necroptosis. Deletion of the proapoptotic Bcl-2 family members Bax and Bak inhibits bone marrow apoptosis. Further deletion of the BH3-only member Bid (to generate triple-knockout [TKO] mice) leads to unrestrained bone marrow necroptosis driven by increased Rip1 kinase (Ripk1). TKO mice display loss of progenitor cells, leading to increased cytokine production and increased stem cell proliferation and exhaustion and culminating in bone marrow failure. Genetically restoring Ripk1 to wild-type levels restores peripheral red cell counts as well as normal cytokine production. TKO bone marrow is hypercellular with abnormal differentiation, resembling the human disorder myelodysplastic syndrome (MDS), and we demonstrate increased necroptosis in MDS bone marrow. Finally, we show that Bid impacts necroptotic signaling through modulation of caspase-8-mediated Ripk1 degradation. Thus, we demonstrate that dysregulated necroptosis in hematopoiesis promotes bone marrow progenitor cell death that incites inflammation, impairs hematopoietic stem cells, and recapitulates the salient features of the bone marrow failure disorder MDS.
© 2019 by The American Society of Hematology.
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15 MeSH Terms
Treatment-Induced Tumor Cell Apoptosis and Secondary Necrosis Drive Tumor Progression in the Residual Tumor Microenvironment through MerTK and IDO1.
Werfel TA, Elion DL, Rahman B, Hicks DJ, Sanchez V, Gonzales-Ericsson PI, Nixon MJ, James JL, Balko JM, Scherle PA, Koblish HK, Cook RS
(2019) Cancer Res 79: 171-182
MeSH Terms: Animals, Antineoplastic Agents, Apoptosis, Female, Indoleamine-Pyrrole 2,3,-Dioxygenase, Inflammation, Lapatinib, Lung Neoplasms, Macrophages, Mammary Neoplasms, Experimental, Mice, Necrosis, Phagocytosis, Receptor, ErbB-2, T-Lymphocytes, Regulatory, Tumor Microenvironment, c-Mer Tyrosine Kinase
Show Abstract · Added April 15, 2019
Efferocytosis is the process by which apoptotic cells are cleared from tissue by phagocytic cells. The removal of apoptotic cells prevents them from undergoing secondary necrosis and releasing their inflammation-inducing intracellular contents. Efferocytosis also limits tissue damage by increasing immunosuppressive cytokines and leukocytes and maintains tissue homeostasis by promoting tolerance to antigens derived from apoptotic cells. Thus, tumor cell efferocytosis following cytotoxic cancer treatment could impart tolerance to tumor cells evading treatment-induced apoptosis with deleterious consequences in tumor residual disease. We report here that efferocytosis cleared apoptotic tumor cells in residual disease of lapatinib-treated HER2 mammary tumors in MMTV-Neu mice, increased immunosuppressive cytokines, myeloid-derived suppressor cells (MDSC), and regulatory T cells (Treg). Blockade of efferocytosis induced secondary necrosis of apoptotic cells, but failed to prevent increased tumor MDSCs, Treg, and immunosuppressive cytokines. We found that efferocytosis stimulated expression of IFN-γ, which stimulated the expression of indoleamine-2,3-dioxegenase (IDO) 1, an immune regulator known for driving maternal-fetal antigen tolerance. Combined inhibition of efferocytosis and IDO1 in tumor residual disease decreased apoptotic cell- and necrotic cell-induced immunosuppressive phenotypes, blocked tumor metastasis, and caused tumor regression in 60% of MMTV-Neu mice. This suggests that apoptotic and necrotic tumor cells, via efferocytosis and IDO1, respectively, promote tumor 'homeostasis' and progression. SIGNIFICANCE: These findings show in a model of HER2 breast cancer that necrosis secondary to impaired efferocytosis activates IDO1 to drive immunosuppression and tumor progression.
©2018 American Association for Cancer Research.
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17 MeSH Terms
Cadherin-11 as a regulator of valve myofibroblast mechanobiology.
Bowler MA, Bersi MR, Ryzhova LM, Jerrell RJ, Parekh A, Merryman WD
(2018) Am J Physiol Heart Circ Physiol 315: H1614-H1626
MeSH Terms: Actins, Animals, Aortic Valve, Cadherins, Cells, Cultured, Focal Adhesions, Interleukin-6, Mechanotransduction, Cellular, Mice, Myofibroblasts, Protein Binding, Tumor Necrosis Factor-alpha
Show Abstract · Added March 18, 2020
Cadherin-11 (CDH11) is upregulated in a variety of fibrotic diseases, including arthritis and calcific aortic valve disease. Our recent work has identified CDH11 as a potential therapeutic target and shown that treatment with a CDH11 functional blocking antibody can prevent hallmarks of calcific aortic valve disease in mice. The present study investigated the role of CDH11 in regulating the mechanobiological behavior of valvular interstitial cells believed to cause calcification. Aortic valve interstitial cells were harvested from Cdh11, Cdh11, and Cdh11 immortomice. Cells were subjected to inflammatory cytokines transforming growth factor (TGF)-β and IL-6 to characterize the molecular mechanisms by which CDH11 regulates their mechanobiological changes. Histology was performed on aortic valves from Cdh11, Cdh11, and Cdh11 mice to identify key responses to CDH11 deletion in vivo. We showed that CDH11 influences cell behavior through its regulation of contractility and its ability to bind substrates via focal adhesions. We also show that transforming growth factor-β overrides the normal relationship between CDH11 and smooth muscle α-actin to exacerbate the myofibroblast disease phenotype. This phenotypic switch is potentiated through the IL-6 signaling axis and could act as a paracrine mechanism of myofibroblast activation in neighboring aortic valve interstitial cells in a positive feedback loop. These data suggest CDH11 is an important mediator of the myofibroblast phenotype and identify several mechanisms by which it modulates cell behavior. NEW & NOTEWORTHY Cadherin-11 influences valvular interstitial cell contractility by regulating focal adhesions and inflammatory cytokine secretion. Transforming growth factor-β overrides the normal balance between cadherin-11 and smooth muscle α-actin expression to promote a myofibroblast phenotype. Cadherin-11 is necessary for IL-6 and chitinase-3-like protein 1 secretion, and IL-6 promotes contractility. Targeting cadherin-11 could therapeutically influence valvular interstitial cell phenotypes in a multifaceted manner.
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MLKL Requires the Inositol Phosphate Code to Execute Necroptosis.
Dovey CM, Diep J, Clarke BP, Hale AT, McNamara DE, Guo H, Brown NW, Cao JY, Grace CR, Gough PJ, Bertin J, Dixon SJ, Fiedler D, Mocarski ES, Kaiser WJ, Moldoveanu T, York JD, Carette JE
(2018) Mol Cell 70: 936-948.e7
MeSH Terms: Binding Sites, Cell Death, Colonic Neoplasms, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, HT29 Cells, Herpesvirus 1, Human, Humans, Inositol Phosphates, Jurkat Cells, Mutation, Phosphorylation, Phosphotransferases (Alcohol Group Acceptor), Protein Kinases, Receptor-Interacting Protein Serine-Threonine Kinases, Signal Transduction, Tumor Necrosis Factor-alpha
Show Abstract · Added March 30, 2020
Necroptosis is an important form of lytic cell death triggered by injury and infection, but whether mixed lineage kinase domain-like (MLKL) is sufficient to execute this pathway is unknown. In a genetic selection for human cell mutants defective for MLKL-dependent necroptosis, we identified mutations in IPMK and ITPK1, which encode inositol phosphate (IP) kinases that regulate the IP code of soluble molecules. We show that IP kinases are essential for necroptosis triggered by death receptor activation, herpesvirus infection, or a pro-necrotic MLKL mutant. In IP kinase mutant cells, MLKL failed to oligomerize and localize to membranes despite proper receptor-interacting protein kinase-3 (RIPK3)-dependent phosphorylation. We demonstrate that necroptosis requires IP-specific kinase activity and that a highly phosphorylated product, but not a lowly phosphorylated precursor, potently displaces the MLKL auto-inhibitory brace region. These observations reveal control of MLKL-mediated necroptosis by a metabolite and identify a key molecular mechanism underlying regulated cell death.
Copyright © 2018 Elsevier Inc. All rights reserved.
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