scholarly journals DRAM Triggers Lysosomal Membrane Permeabilization and Cell Death in CD4+ T Cells Infected with HIV

2013 ◽  
Vol 9 (5) ◽  
pp. e1003328 ◽  
Author(s):  
Mireille Laforge ◽  
Sophie Limou ◽  
Francis Harper ◽  
Nicoletta Casartelli ◽  
Vasco Rodrigues ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Cd4 T Cells ◽  
Membrane Permeabilization ◽  
Lysosomal Membrane ◽  
Lysosomal Membrane Permeabilization

scholarly journals Increased Lysosomal Membrane Permeabilization in Oxidant-exposed Macrophages of Human Fibrotic Lungs

2013 ◽  
Vol 6 ◽  
pp. JCD.S13271 ◽  
Author(s):  
Hans L Persson ◽  
Linda K. Vainikka
Keyword(s):  
Cell Death ◽  
Lung Fibrosis ◽  
Reduced Glutathione ◽  
Atomic Absorption Spectrophotometry ◽  
Membrane Permeabilization ◽  
Lysosomal Membrane ◽  
Blue Staining ◽  
Green Fluorescence ◽  
Lysosomal Membrane Permeabilization ◽  
Typical Morphology

A disrupted balance of reduced glutathione (GSH) and iron (Fe) and subsequent enhanced susceptibility of lysosomes of lung macrophages (LMs) to oxidants may play a role in lung fibrogenesis. We assessed cellular Fe/GSH, lysosomal membrane permeabilization (LMP), and cell death in cultures of oxidant exposed LMs. LMs from 7 lung fibrosis patients and healthy subjects were exposed to a physiologic concentration of H2O2 for 1 h. LMP was assessed with acridine orange green fluorescence, apoptosis/necrosis were estimated by apoptotic DNA and typical morphology, Fe was assessed with Prussian blue staining/atomic absorption spectrophotometry, and GSH was evaluated using a GSH assay kit. Oxidant-induced LMP and cell death were more pronounced in cultures of LMs from patients with lung fibrosis, and these cells contained less GSH and more cytochemically stained Fe. These observations indicate that LMP may be involved in fibrosis development, possibly through activation of the inflammasome complex. Further studies are warranted for a detailed understanding.

Lysosomes in programmed cell death pathways: from initiators to amplifiers

2017 ◽  
Vol 398 (3) ◽  
pp. 289-301 ◽  
Author(s):  
Nežka Kavčič ◽  
Katarina Pegan ◽  
Boris Turk
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Membrane Permeabilization ◽  
Lysosomal Membrane ◽  
Inflammasome Activation ◽  
Biological Macromolecules ◽  
Lysosomal Hydrolases ◽  
Lysosomal Membrane Permeabilization ◽  
Cell Death Pathways ◽  
Major Attention

Abstract Lysosome is the central organelle for intracellular degradation of biological macromolecules and organelles. The material destined for degradation enters the lysosomes primarily via endocytosis, autophagy and phagocytosis, and is degraded through the concerted action of more than 50 lysosomal hydrolases. However, lysosomes are also linked with numerous other processes, including cell death, inflammasome activation and immune response, as well as with lysosomal secretion and cholesterol recycling. Among them programmed cell death pathways including apoptosis have received major attention. In most of these pathways, cell death was accompanied by lysosomal membrane permeabilization and release of lysosomal constituents with an involvement of lysosomal hydrolases, including the cathepsins. However, it is less clear, whether lysosomal membrane permeabilization is really critical for the initiation of cell death programme(s). Therefore, the role of lysosomal membrane permeabilization in various programmed cell death pathways is reviewed, as well as the mechanisms leading to it.

scholarly journals Inhibition of Sp1 prevents ER homeostasis and causes cell death by lysosomal membrane permeabilization in pancreatic cancer

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Patricia Dauer ◽  
Vineet K. Gupta ◽  
Olivia McGinn ◽  
Alice Nomura ◽  
Nikita S. Sharma ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Death ◽  
Membrane Permeabilization ◽  
Lysosomal Membrane ◽  
Lysosomal Membrane Permeabilization ◽  
Er Homeostasis

GDC-0941 enhances the lysosomal compartment via TFEB and primes glioblastoma cells to lysosomal membrane permeabilization and cell death

2013 ◽  
Vol 329 (1) ◽  
pp. 27-36 ◽  
Author(s):  
Stefanie Enzenmüller ◽  
Patrick Gonzalez ◽  
Georg Karpel-Massler ◽  
Klaus-Michael Debatin ◽  
Simone Fulda
Keyword(s):  
Cell Death ◽  
Membrane Permeabilization ◽  
Lysosomal Membrane ◽  
Glioblastoma Cells ◽  
Lysosomal Compartment ◽  
Lysosomal Membrane Permeabilization

scholarly journals Lysosomal Membrane Permeabilization Induces Cell Death in a Mitochondrion-dependent Fashion

2003 ◽  
Vol 197 (10) ◽  
pp. 1323-1334 ◽  
Author(s):  
Patricia Boya ◽  
Karine Andreau ◽  
Delphine Poncet ◽  
Naoufal Zamzami ◽  
Jean-Luc Perfettini ◽  
...  
Keyword(s):  
Cell Death ◽  
Uv Light ◽  
Chromatin Condensation ◽  
Cell Loss ◽  
Membrane Permeabilization ◽  
Lysosomal Membrane ◽  
Cytotoxic Action ◽  
Double Knockout ◽  
Lysosomal Membrane Permeabilization ◽  
Mitochondrial Membrane Permeabilization

A number of diseases are due to lysosomal destabilization, which results in damaging cell loss. To investigate the mechanisms of lysosomal cell death, we characterized the cytotoxic action of two widely used quinolone antibiotics: ciprofloxacin (CPX) or norfloxacin (NFX). CPX or NFX plus UV light (NFX*) induce lysosomal membrane permeabilization (LMP), as detected by the release of cathepsins from lysosomes. Inhibition of the lysosomal accumulation of CPX or NFX suppresses their capacity to induce LMP and to kill cells. CPX- or NFX-triggered LMP results in caspase-independent cell death, with hallmarks of apoptosis such as chromatin condensation and phosphatidylserine exposure on the plasma membrane. LMP triggers mitochondrial membrane permeabilization (MMP), as detected by the release of cytochrome c. Both CPX and NFX* cause Bax and Bak to adopt their apoptotic conformation and to insert into mitochondrial membranes. Bax−/− Bak−/− double knockout cells fail to undergo MMP and cell death in response to CPX- or NFX-induced LMP. The single knockout of Bax or Bak (but not Bid) or the transfection-enforced expression of mitochondrion-targeted (but not endoplasmic reticulum–targeted) Bcl-2 conferred protection against CPX (but not NFX*)-induced MMP and death. Altogether, our data indicate that mitochondria are indispensable for cell death initiated by lysosomal destabilization.

scholarly journals Lysosomal Cell Death and Apoptosis Crosstalk - Synergistic Role in Bcl-2 Inhibitor (ABT-263) Mediated Cell Death in B-Cell Precursor Acute Lymphoblastic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1584-1584
Author(s):  
Stefanie Enzenmüller ◽  
Qian Sun ◽  
Klaus-Michael Debatin ◽  
Lüder-Hinrich Meyer
Keyword(s):  
Cell Death ◽  
Lymphoblastic Leukemia ◽  
Membrane Integrity ◽  
Membrane Permeabilization ◽  
Lysosomal Membrane ◽  
Secondary Effect ◽  
Cell Precursor ◽  
Apoptosis Pathway ◽  
Lysosomal Membrane Permeabilization ◽  
Lysosomal Membrane Integrity

Abstract Although improved treatment of pediatric Acute Lymphoblastic Leukemia (ALL) has become increasingly successful with cure rates of up to 90%, leukemia reoccurrence is clearly associated with inferior prognosis. Treatment failure and resistance in leukemias are considered to involve defects in apoptosis signaling, which forms the basis for apoptogenic treatment approaches such as the use of Bcl-2 inhibitors. Identification of alternative cell death programs like lysosomal membrane permeabilization-induced cell death may provide a novel strategy for the treatment of ALL. Previous studies showed that lysosomal activity, as well as their traffic properties are greatly altered during tumorigenesis. Intralysosomal hydrolases such as cathepsin B, L and D have been implicated in cancer progression and high expression levels are generally associated with poor prognosis. Lysosomotropic agents modulating lysosomal integrity may overcome cell death resistance and might therefore also improve the outcome of high risk or ALL relapse patients. In this study, we investigated the efficacy of the lysosomotropic compound B10, a derivative of Betulinic acid, as well as its combination with the Bcl-2 inhibitor ABT-263 in B-cell precursor- (BCP-) ALL. In BCP-ALL cell lines, B10 showed induction of cell death combined with increased DNA fragmentation. Interestingly, additional treatment with the pan-caspase inhibitor zVAD.fmk only partially rescued B10 triggered loss of cell viability, indicating that B10 is not exclusively inducing caspase-dependent apoptosis, but also induces an additional alternative cell death program. B10 permeabilized lysosomes as indicated by the significant decrease of LysotrackerRED positive populations detected by flow cytometry, and treatment with E-64d, a potent inhibitor of thiol proteases and cathepsins, reduced B10-induced cell death, thus emphasizing the cathepsin-dependent effect of B10. To exclude that B10-induced lysosomal permeabilization might represent a secondary effect, a panel of different substances was tested for their activity on lysosomal membrane integrity. While treatment with dexamethasone, chloroquine, vincristine and asparaginase also showed lysosomal permeabilization, co-treatment with E-64d did not reduce cell death indicating a secondary effect of these compounds on lysosomes. In addition to cell lines, we tested the effect of B10 on 15 primary leukemia samples isolated from ALL bearing mice of established patient-derived NOD/SCID/hu BCP-ALL xenografts. In a majority of these individual patient-derived leukemias, B10 induced cell death that could be inhibited by E-64d, thus demonstrating a lysosomal protease-dependent death program also in primary ALL. In addition to its classical role in triggering the intrinsic mitochondria dependent apoptosis pathway, the pro-apoptotic Bcl-2 family member Bax was previously described to be involved in the regulation of lysosomal membrane integrity, pointing to a possible synergistic effect of B10 and BH3-mimetics. Intriguingly, in cell fractionation assays we observed increased Bax recruitment to lysosomal membranes when B10 is present. Interestingly, co-treatment with the Bcl-2 inhibitor ABT-263, which displaces Bcl-2 from its inhibitory binding to Bax, led to increased lysosomal permeabilization, loss of mitochondrial membrane potential, and caspase activation indicating involvement of the intrinsic apoptosis pathway. The importance of lysosomal Bax recruitment for the activity of ABT-263 and its concomitant effect on lysosomal membrane permeabilization was further supported by Bax knockdown experiments, since induction of lysosomal disruption, release of cathepsins and their subsequent effect on cell death activation by B10 was reduced. Taken together, our findings suggest an important role of lysosomal membrane permeabilization-induced cell death for the activity of Bcl-2 inhibitors such as ABT-263. The combination of BH3 mimetics with lysosomotropic compounds may provide the basis for novel molecular directed treatment strategies. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document