VDAC-dependent permeabilization of the outer mitochondrial membrane by superoxide induces rapid and massive cytochrome c release.
AuthorsMadesh M, Hajnóczky G
JournalJ Cell Biol
PubMed ID11739410
'Enhanced formation of reactive oxygen species (ROS), superoxide (O2*-), and hydrogen peroxide (H2O2) may result in either apoptosis or other forms of cell death. Here, we studied the mechanisms underlying activation of the apoptotic machinery by ROS. Exposure of permeabilized HepG2 cells to O2*- elicited rapid and massive cytochrome c ... More
Cyclopentenone prostaglandins of the J series inhibit the ubiquitin isopeptidase activity of the proteasome pathway.
AuthorsMullally JE, Moos PJ, Edes K, Fitzpatrick FA
JournalJ Biol Chem
PubMed ID11390388
'Electrophilic eicosanoids of the J series, with their distinctive cross-conjugated alpha,beta-unsaturated ketone, inactivate genetically wild type tumor suppressor p53 in a manner analogous to prostaglandins of the A series. Like the prostaglandins of the A series, prostaglandins of the J series have a structural determinant (endocyclic cyclopentenone) that confers the ... More
Aberrant T cell differentiation in the absence of Dicer.
AuthorsMuljo SA, Ansel KM, Kanellopoulou C, Livingston DM, Rao A, Rajewsky K
JournalJ Exp Med
PubMed ID16009718
'Dicer is an RNaseIII-like enzyme that is required for generating short interfering RNAs and microRNAs. The latter have been implicated in regulating cell fate determination in invertebrates and vertebrates. To test the requirement for Dicer in cell-lineage decisions in a mammalian organism, we have generated a conditional allele of dicer-1 ... More
Free cholesterol loading of macrophages induces apoptosis involving the fas pathway.
AuthorsYao PM, Tabas I
JournalJ Biol Chem
PubMed ID10791964
'Macrophage death is an important feature of atherosclerosis, but the cellular mechanism for this process is largely unknown. There is increasing interest in cellular free cholesterol (FC) excess as an inducer of lesional macrophage death because macrophages accumulate large amounts of FC in vivo, and FC loading of macrophages in ... More
Proteolytic activation of protein kinase C-epsilon by caspase-mediated processing and transduction of antiapoptotic signals.
AuthorsBasu A, Lu D, Sun B, Moor AN, Akkaraju GR, Huang J,
JournalJ Biol Chem
PubMed ID12198125
'Several novel protein kinase C (PKC) isozymes have been identified as substrates for caspase-3. We have previously shown that novel PKCepsilon is cleaved during apoptosis in MCF-7 cells that lack any functional caspase-3. In the present study, we show that in vitro-translated PKCepsilon is processed by human recombinant caspase-3, -7, ... More
Redox-proteomic analysis of doxorubicin-induced altered thiol activity in cardiomyocytes.
AuthorsLin ST, Chou HC, Chen YW, Chan HL
JournalMol Biosyst
PubMed ID23340498
'Doxorubicin is an anticancer drug used in a wide range of cancer therapies, yet some side effects have been reported. One of these is cardiotoxicity, including cardiomyopathy and ultimately congestive heart failure. This damage to the heart has been shown to result from doxorubicin-induced reactive oxygen species. However, the cellular ... More
Pathways of proximal tubular cell death in bismuth nephrotoxicity.
AuthorsLeussink BT, Nagelkerke JF, van de Water B, Slikkerveer A, van der Voet GB, Srinivasan A, Bruijn JA, de Wolff FA, de Heer E
JournalToxicol Appl Pharmacol
PubMed ID11969377
'Colloidal bismuth subcitrate (CBS), a drug for treatment of peptic ulcers, has been reported in the literature to be nephrotoxic in humans when taken in high overdoses. To investigate the mechanism of bismuth nephropathy, we developed an animal model by feeding rats single doses of CBS containing 3.0 mmol Bi/kg ... More
Distinct phosphoinositide 3-kinases mediate mast cell degranulation in response to G-protein-coupled versus FcepsilonRI receptors.
AuthorsWindmiller DA, Backer JM
JournalJ Biol Chem
PubMed ID12529321
'Phosphoinositide (PI) 3-kinases are critical regulators of mast cell degranulation. The Class IA PI 3-kinases p85/p110beta and p85/p110delta but not p85/p110alpha are required for antigen-mediated calcium flux in RBL-2H3 cells (Smith, A. J., Surviladze, Z., Gaudet, E. A., Backer, J. M., Mitchell, C. A., and Wilson, B. S. et al., ... More
Cholesterol-induced apoptotic macrophages elicit an inflammatory response in phagocytes, which is partially attenuated by the Mer receptor.
AuthorsLi Y, Gerbod-Giannone MC, Seitz H, Cui D, Thorp E, Tall AR, Matsushima GK, Tabas I
JournalJ Biol Chem
PubMed ID16380374
'Macrophage apoptosis and the ability of phagocytes to clear these apoptotic cells are important processes in advanced atherosclerosis. Phagocytic clearance not only disposes of dead cells but usually elicits an anti-inflammatory response. To study this process in a model of advanced lesional macrophage death, macrophages rendered apoptotic by free cholesterol ... More
Inhibition of deoxycholate-induced apoptosis in iron-depleted HCT-116 cells.
AuthorsLongpre J, Loo G
JournalApoptosis
PubMed ID21938477
'The bile acid, deoxycholate (DOC), can induce apoptosis in cells containing adequate amounts of all key nutrients, but it is unknown whether DOC-induced apoptosis can occur in cells lacking a single key nutrient. The aim of this study was to determine if DOC is able to induce apoptosis in HCT-116 ... More
Disruption of mitochondria during tocotrienol-induced apoptosis in MDA-MB-231 human breast cancer cells.
AuthorsTakahashi K, Loo G
JournalBiochem Pharmacol
PubMed ID14698044
'Tocotrienols, which are Vitamin E isoforms, are known to inhibit the growth of human breast cancer cells due partly to apoptosis. However, the characterization of tocotrienol-induced apoptosis is incomplete, particularly what happens during the initiation phase that precedes execution of the cells. The objective of this study was to clarify ... More
Protein kinase Cepsilon activates protein kinase B/Akt via DNA-PK to protect against tumor necrosis factor-alpha-induced cell death.
AuthorsLu D, Huang J, Basu A
JournalJ Biol Chem
PubMed ID16785234
'We have previously shown that protein kinase Cepsilon (PKCepsilon) protects breast cancer cells from tumor necrosis factor-alpha (TNF)-induced cell death. In the present study, we have investigated if the antiapoptotic function of PKCepsilon is mediated via Akt and the mechanism by which PKCepsilon regulates Akt activity. TNF caused a transient ... More
Accumulation of glycosphingolipids in Niemann-Pick C disease disrupts endosomal transport.
Authorste Vruchte D, Lloyd-Evans E, Veldman RJ, Neville DC, Dwek RA, Platt FM, van Blitterswijk WJ, Sillence DJ
JournalJ Biol Chem
PubMed ID15078881
'Glycosphingolipids are endocytosed and targeted to the Golgi apparatus but are mistargeted to lysosomes in sphingolipid storage disorders. Substrate reduction therapy utilizes imino sugars to inhibit glucosylceramide synthase and potentially abrogate the effects of storage. Niemann-Pick type C (NPC) disease is a disorder of intracellular transport where glycosphingolipids (GSLs) and ... More
Synthesis and identification of small molecules that potently induce apoptosis in melanoma cells through G1 cell cycle arrest.
'Late-stage malignant melanoma is a cancer that is refractory to current chemotherapeutic treatments. The average survival time for patients with such a diagnosis is 6 months. In general, the vast majority of anticancer drugs operate through induction of cell cycle arrest and cell death in either the DNA synthesis (S) ... More
Endocytosis is enhanced in Tangier fibroblasts: possible role of ATP-binding cassette protein A1 in endosomal vesicular transport.
AuthorsZha X, Genest J, McPherson R
JournalJ Biol Chem
PubMed ID11504722
'A human genetic disorder, Tangier disease, has been linked recently to mutations in ATP-binding cassette protein A1 (ABCA1). In addition to its function in apoprotein A-I-mediated lipid removal, ABCA1 was also shown to be a phosphatidylserine (PS) translocase that facilitates PS exofacial flipping. This PS translocation is crucial for the ... More
High-throughput screening of cell death inducible short peptides from TNF-related apoptosis-inducing ligand sequence.
AuthorsOkochi M, Nakanishi M, Kato R, Kobayashi T, Honda H
JournalFEBS Lett
PubMed ID16427631
Therapeutic peptides and small molecules, rationally designed to trigger cell death have attracted strong attention. Cell death inducible peptides were screened from amino acid sequence of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Using Fmoc solid phase synthesis, cellulose membrane-bound octameric peptide library of TRAIL scan was prepared and cell viability ... More
Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets.
AuthorsJosefsson EC, James C, Henley KJ, Debrincat MA, Rogers KL, Dowling MR, White MJ, Kruse EA, Lane RM, Ellis S, Nurden P, Mason KD, O'Reilly LA, Roberts AW, Metcalf D, Huang DC, Kile BT,
JournalJ Exp Med
PubMed ID21911424
It is believed that megakaryocytes undergo a specialized form of apoptosis to shed platelets. Conversely, a range of pathophysiological insults, including chemotherapy, are thought to cause thrombocytopenia by inducing the apoptotic death of megakaryocytes and their progenitors. To resolve this paradox, we generated mice with hematopoietic- or megakaryocyte-specific deletions of ... More
Single-step process to reconstitute cell membranes on solid supports.
AuthorsMager MD, Melosh NA,
JournalLangmuir
PubMed ID20205459
A new technique is presented to create supported lipid bilayers from whole cell lipids without the use of detergent or solvent extraction. In a modification of the bubble collapse deposition (BCD) technique, an air bubble is created underwater and brought into contact with a population of cells. The high-energy air/water ... More
Conventional apoptosis assays using propidium iodide generate a significant number of false positives that prevent accurate assessment of cell death.
AuthorsRieger AM, Hall BE, Luong le T, Schang LM, Barreda DR,
JournalJ Immunol Methods
PubMed ID20381494
The advent of flow cytometry-based applications has significantly impacted the study of cellular apoptosis. Propidium iodide (PI) is a commonly used viability stain in these studies. Unfortunately, we find that conventional Annexin V/PI protocols lead to a significant number of false positive events (up to 40%), which are associated with ... More
Pivotal advance: macrophages become resistant to cholesterol-induced death after phagocytosis of apoptotic cells.
AuthorsCui D, Thorp E, Li Y, Wang N, Yvan-Charvet L, Tall AR, Tabas I,
JournalJ Leukoc Biol
PubMed ID17576822
One of the most important functions of macrophages is the phagocytosis of apoptotic cells (ACs). ACs deliver large amounts membrane-derived cholesterol to phagocytes, which, if not handled properly, can be cytotoxic. In atherosclerosis, where the ACs are cholesterol-loaded, this situation is exaggerated, because the ACs deliver both endogenous membrane cholesterol ... More
Markers of apoptosis: methods for elucidating the mechanism of apoptotic cell death from the nervous system.
AuthorsSmyth PG, Berman SA,
JournalBiotechniques
PubMed ID11911667
Apoptosis is a highly conserved energy-requiring program for non-inflammatory cell death that is important in both normal physiology and disease. Numerous techniques have been used to study apoptosis. In the nervous system, apoptosis is necessary for normal development, but it also occurs in many acute and chronic pathologic conditions. This ... More
Extracellular adenosine-induced apoptosis in mouse neuroblastoma cells: studies on involvement of adenosine receptors and adenosine uptake.
AuthorsSchrier SM, van Tilburg EW, van der Meulen H, Ijzerman AP, Mulder GJ, Nagelkerke JF
JournalBiochem Pharmacol
PubMed ID11226375
The induction of apoptosis by adenosine was studied in the mouse neuroblastoma cell line N1E-115. Apoptosis was characterized by fluorescence and electron microscopy, fluorescence-activated cell sorter (FACS) analysis, and caspase activity assays. A sixteen-hour exposure to 100 microM of adenosine led to chromatin condensation and caspase activation. However, selective agonists ... More
C. elegans mitochondrial factor WAH-1 promotes phosphatidylserine externalization in apoptotic cells through phospholipid scramblase SCRM-1.
AuthorsWang X, Wang J, Gengyo-Ando K, Gu L, Sun CL, Yang C, Shi Y, Kobayashi T, Shi Y, Mitani S, Xie XS, Xue D
JournalNat Cell Biol
PubMed ID17401362
Externalization of phosphatidylserine, which is normally restricted to the inner leaflet of plasma membrane, is a hallmark of mammalian apoptosis. It is not known what activates and mediates the phosphatidylserine externalization process in apoptotic cells. Here, we report the development of an annexin V-based phosphatidylserine labelling method and show that ... More
Small-molecule activation of procaspase-3 to caspase-3 as a personalized anticancer strategy.
Mutation and aberrant expression of apoptotic proteins are hallmarks of cancer. These changes prevent proapoptotic signals from being transmitted to executioner caspases, thereby averting apoptotic death and allowing cellular proliferation. Caspase-3 is the key executioner caspase, and it exists as an inactive zymogen that is activated by upstream signals. Notably, ... More
Early and late cytotoxic effects of external application of the Alzheimer's Abeta result from the initial formation and function of Abeta ion channels.
AuthorsSimakova O, Arispe NJ
JournalBiochemistry
PubMed ID16669633
Extracellular application of the Alzheimer's beta-amyloid (Abeta) peptide evokes a series of cellular responses that leads to the death of cells by apoptosis. Some responses to freshly prepared Abeta occur immediately, including changes in intracellular calcium concentration and changes in membrane permeability and phosphatidylserine asymmetry. We show here that the ... More
Amyloid fibrils of mammalian prion protein are highly toxic to cultured cells and primary neurons.
AuthorsNovitskaya V, Bocharova OV, Bronstein I, Baskakov IV
JournalJ Biol Chem
PubMed ID16554307
A growing body of evidence indicates that small, soluble oligomeric species generated from a variety of proteins and peptides rather than mature amyloid fibrils are inherently highly cytotoxic. Here, we show for the first time that mature amyloid fibrils produced from full-length recombinant mammalian prion protein (rPrP) were highly toxic ... More
Dual-targeting immunotherapy of lymphoma: potent cytotoxicity of anti-CD20/CD74 bispecific antibodies in mantle cell and other lymphomas.
We describe the use of novel bispecific hexavalent Abs (HexAbs) to enhance anticancer immunotherapy. Two bispecific HexAbs [IgG-(Fab)(4) constructed from veltuzumab (anti-CD20 IgG) and milatuzumab (anti-CD74 IgG)] show enhanced cytotoxicity in mantle cell lymphoma (MCL) and other lymphoma/leukemia cell lines, as well as patient tumor samples, without a crosslinking Ab, ... More
Exposure to airborne particulate matter (PM) is a world-wide health problem mainly because it produces adverse cardiovascular and respiratory effects that frequently result in morbidity. Despite many years of epidemiological and basic research, the mechanisms underlying PM toxicity remain largely unknown. To understand some of these mechanisms, we measured PM-induced ... More
Ceramide-induced TCR up-regulation.
AuthorsMenné C, Lauritsen JP, Dietrich J, Kastrup J, Wegener AM, Odum N, Geisler C
JournalJ Immunol
PubMed ID10975817
The TCR is a constitutively recycling receptor meaning that a constant fraction of TCR from the plasma membrane is transported inside the cell at the same time as a constant fraction of TCR from the intracellular pool is transported to the plasma membrane. TCR recycling is affected by protein kinase ... More
Mitochondrial superoxide radicals mediate programmed cell death in Trypanosoma cruzi: cytoprotective action of mitochondrial iron superoxide dismutase overexpression.
AuthorsPiacenza L, Irigoín F, Alvarez MN, Peluffo G, Taylor MC, Kelly JM, Wilkinson SR, Radi R
JournalBiochem J
PubMed ID17168856
Trypanosoma cruzi undergo PCD (programmed cell death) under appropriate stimuli, the mechanisms of which remain to be established. In the present study, we show that stimulation of PCD in T. cruzi epimastigotes by FHS (fresh human serum) results in rapid (<1 h) externalization of phosphatidylserine and depletion of the low ... More
Two phases of signalling between mitochondria during apoptosis leading to early depolarisation and delayed cytochrome c release.
AuthorsLum MG, Nagley P
JournalJ Cell Sci
PubMed ID12640029
We investigated the mode of signalling between mitochondria during apoptosis by monitoring the behaviour of non-irradiated mitochondria following microscopic photosensitisation of half the mitochondria in single human osteosarcoma cells loaded with CMXRos. Following partial irradiation of cells, non-irradiated mitochondria underwent a rapid depolarisation (within 10 minutes). The depolarisation was not ... More
Aplidin induces apoptosis in human cancer cells via glutathione depletion and sustained activation of the epidermal growth factor receptor, Src, JNK, and p38 MAPK.
AuthorsCuadrado A, Garcia-Fernandez LF, Gonzalez L, Suarez Y, Losada A, Alcaide V, Martinez T, Fernandez-Sousa JM, Sanchez-Puelles JM, Munoz A
JournalJ Biol Chem
PubMed ID12414812
We report that Aplidin, a novel antitumor agent of marine origin presently undergoing Phase II clinical trials, induced growth arrest and apoptosis in human MDA-MB-231 breast cancer cells at nanomolar concentrations. Aplidin induced a specific cellular stress response program, including sustained activation of the epidermal growth factor receptor (EGFR), the ... More
Coverslip hypoxia: a novel method for studying cardiac myocyte hypoxia and ischemia in vitro.
AuthorsPitts KR, Toombs CF
JournalAm J Physiol Heart Circ Physiol
PubMed ID15155258
In vitro experimental models designed to study the effects of hypoxia and ischemia typically employ oxygen-depleted media and/or hypoxic chambers. These approaches, however, allow for metabolites to diffuse away into a large volume and may not replicate the high local concentrations that occur in ischemic myocardium in vivo. We describe ... More
Octa-arginine-modified pegylated liposomal doxorubicin: an effective treatment strategy for non-small cell lung cancer.
The present study aims to evaluate the efficacy of octa-arginine (R8)-modified pegylated liposomal doxorubicin (R8-PLD) for the treatment of non-small cell lung cancer, for which the primary treatment modality currently consists of surgery and radiotherapy. Cell-penetrating peptide R8 modification of Doxorubicin-(Dox)-loaded liposomes was performed by post-insertion of an R8-conjugated amphiphilic ... More
Free cholesterol loading of macrophages is associated with widespread mitochondrial dysfunction and activation of the mitochondrial apoptosis pathway.
AuthorsYao PM, Tabas I
JournalJ Biol Chem
PubMed ID11533046
Macrophage death in advanced atherosclerotic lesions leads to lesional necrosis and possibly plaque rupture and acute vascular occlusion. Among the likely causes of lesional macrophage death is intracellular accumulation of excess free cholesterol (FC), which is known to occur in vivo. We recently showed that FC loading of macrophages causes ... More
Surface functionalization of doxorubicin-loaded liposomes with octa-arginine for enhanced anticancer activity.
Doxorubicin-loaded PEGylated liposomes (commercially available as DOXIL or Lipodox) were surface functionalized with a cell-penetrating peptide, octa-arginine (R8). For this purpose, R8-peptide was conjugated to the polyethylene glycol-dioleoyl phosphatidylethanolamine (PEG-DOPE) amphiphilic co-polymer. The resultant R8-PEG-PE conjugate was introduced into the lipid bilayer of liposomes at 2 mol% of total lipid ... More
Macrophages deficient in CTP:Phosphocholine cytidylyltransferase-alpha are viable under normal culture conditions but are highly susceptible to free cholesterol-induced death. Molecular genetic evidence that the induction of phosphatidylcholine biosynthesis in free cholesterol-loaded macrophages is an adaptive response.
AuthorsZhang D, Tang W, Yao PM, Yang C, Xie B, Jackowski S, Tabas I
JournalJ Biol Chem
PubMed ID10944538
Macrophages in atherosclerotic lesions accumulate excess free cholesterol (FC) and phospholipid. Because excess FC is toxic to macrophages, these observations may have relevance to macrophage death and necrosis in atheromata. Previous work by us showed that at early stages of FC loading, when macrophages are still healthy, there is activation ... More
Membrane associated collagen XIII promotes cancer metastasis and enhances anoikis resistance.
AuthorsZhang H, Fredericks T, Xiong G, Qi Y, Rychahou PG, Li JD, Pihlajaniemi T, Xu W, Xu R
JournalBreast Cancer Res
PubMed ID30285809
'Increased collagen expression and deposition are associated with cancer progression and poor prognosis in breast cancer patients. However, function and regulation of membrane-associated collagen in breast cancer have not been determined. Collagen XIII is a type II transmembrane protein within the collagen superfamily. Experiments in tissue culture and knockout mouse ... More
A Two-Cell Model for IL-1ß Release Mediated by Death-Receptor Signaling.
AuthorsDonado CA, Cao AB, Simmons DP, Croker BA, Brennan PJ, Brenner MB
JournalCell Rep
PubMed ID32268091
'Interleukin-1ß (IL-1ß) is a key orchestrator of anti-microbial immunity whose secretion is typically dependent on activation of inflammasomes. However, many pathogens have evolved strategies to evade inflammasome activation. Here we describe an alternative, two-cell model for IL-1ß release where invariant natural killer T (iNKT) cells use the death receptor pathway ... More
Melittin Induced G1 Cell Cycle Arrest and Apoptosis in Chago-K1 Human Bronchogenic Carcinoma Cells and Inhibited the Differentiation of THP-1 Cells into Tumour- Associated Macrophages
AuthorsTipgomut C, Wongprommoon A, Takeo E, Ittiudomrak T, Puthong S, Chanchao C
JournalAsian Pac J Cancer Prev
PubMed ID30583665
Background: Bronchogenic carcinoma (lung cancer) is one of the leading causes of death. Although many
compounds isolated from natural products have been used to treat it, drug resistance is a serious problem, and alternative
anti-cancer drugs are required. Here, melittin from Apis mellifera venom was used, and its effects on bronchogenic
carcinoma cell ... More
Characterisation of the Ral GTPase inhibitor RBC8 in human and mouse platelets.
AuthorsWalsh TG, Wersäll A, Poole AW
JournalCell Signal
PubMed ID30880223
The Ral GTPases, RalA and RalB, have been implicated in numerous cellular processes, but are most widely known for having regulatory roles in exocytosis. Recently, we demonstrated that deletion of both Ral genes in a platelet-specific mouse gene knockout caused a substantial defect in surface exposure of P-selectin, with only ... More