scholarly journals The BH3 mimetic HA14-1 enhances 5-fluorouracil-induced autophagy and type II cell death in oesophageal cancer cells

2012 ◽  
Vol 106 (4) ◽  
pp. 711-718 ◽  
Author(s):  
M J Nyhan ◽  
T R O'Donovan ◽  
B Elzinga ◽  
L C Crowley ◽  
G C O'Sullivan ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Oesophageal Cancer ◽  
Type Ii ◽  
Type Ii Cell ◽  
Bh3 Mimetic

Cytotoxic effects of cigarette smoke extract on an alveolar type II cell-derived cell line

2001 ◽  
Vol 281 (2) ◽  
pp. L509-L516 ◽  
Author(s):  
Yuma Hoshino ◽  
Tadashi Mio ◽  
Sonoko Nagai ◽  
Hiroyuki Miki ◽  
Isao Ito ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Line ◽  
Cigarette Smoke ◽  
A549 Cells ◽  
Cigarette Smoke Extract ◽  
Alveolar Type ◽  
Type Ii ◽  
Cytotoxic Effects ◽  
Alveolar Type Ii Cell ◽  
Type Ii Cell

Injury of the alveolar epithelium by cigarette smoke is presumed to be an important process in the pathogenesis of smoking-related pulmonary diseases. We investigated the cytotoxic effects of cigarette smoke extract (CSE) on an alveolar type II cell-derived cell line (A549). CSE caused apoptosis at concentrations of 5% or less and necrosis at 10% or more. When CSE was exposed to air before application to A549 cells, the cytotoxic effects were attenuated. CSE caused cell death without direct contact with the cells. Acrolein and hydrogen peroxide, two major volatile factors in cigarette smoke, caused cell death in a similar manner. Aldehyde dehydrogenase, a scavenger of aldehydes, and N-acetylcysteine, a scavenger of oxidants and aldehydes, completely inhibited CSE-induced apoptosis. CSE and acrolein increased intracellular oxidant activity. In conclusion, apoptosis of alveolar epithelial cells may be one of the mechanisms of lung injury induced by cigarette smoking. This cytotoxic effect might be due to an interaction between aldehydes and oxidants present in CSE or formed in CSE-exposed cells.

Life, death and burial: multifaceted impact of autophagy

2008 ◽  
Vol 36 (5) ◽  
pp. 786-790 ◽  
Author(s):  
Lorenzo Galluzzi ◽  
Eugenia Morselli ◽  
José Miguel Vicencio ◽  
Oliver Kepp ◽  
Nicholas Joza ◽  
...  
Keyword(s):  
Cell Death ◽  
Normal Development ◽  
Whole Body ◽  
Causative Role ◽  
Type Ii ◽  
Survival Mechanism ◽  
Metabolic Substrates ◽  
Type Ii Cell ◽  
Intracellular Organelles ◽  
Massive Accumulation

Macroautophagy, often referred to as autophagy, designates the process by which portions of the cytoplasm, intracellular organelles and long-lived proteins are engulfed in double-membraned vacuoles (autophagosomes) and sent for lysosomal degradation. Basal levels of autophagy contribute to the maintenance of intracellular homoeostasis by ensuring the turnover of supernumerary, aged and/or damaged components. Under conditions of starvation, the autophagic pathway operates to supply cells with metabolic substrates, and hence represents an important pro-survival mechanism. Moreover, autophagy is required for normal development and for the protective response to intracellular pathogens. Conversely, uncontrolled autophagy is associated with a particular type of cell death (termed autophagic, or type II) that is characterized by the massive accumulation of autophagosomes. Regulators of apoptosis (e.g. Bcl-2 family members) also modulate autophagy, suggesting an intimate cross-talk between these two degradative pathways. It is still unclear whether autophagic vacuolization has a causative role in cell death or whether it represents the ultimate attempt of cells to cope with lethal stress. For a multicellular organism, autophagic cell death might well represent a pro-survival mechanism, by providing metabolic supplies during whole-body nutrient deprivation. Alternatively, type II cell death might contribute to the disposal of cell corpses when heterophagy is deficient. Here, we briefly review the roles of autophagy in cell death and its avoidance.

Hyperoxia-induced apoptosis and Fas/FasL expression in lung epithelial cells

2005 ◽  
Vol 289 (4) ◽  
pp. L647-L659 ◽  
Author(s):  
Monique E. De Paepe ◽  
Quanfu Mao ◽  
Yvonne Chao ◽  
Jessica L. Powell ◽  
Lewis P. Rubin ◽  
...  
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Protein Expression ◽  
Cell Apoptosis ◽  
Receptor Activation ◽  
Type Ii ◽  
Fasl Expression ◽  
Alveolar Epithelial ◽  
Type Ii Cell ◽  
Induced Apoptosis

Alveolar epithelial apoptosis is an important feature of hyperoxia-induced lung injury in vivo and has been described in the early stages of bronchopulmonary dysplasia (chronic lung disease of preterm newborn). Molecular regulation of hyperoxia-induced alveolar epithelial cell death remains incompletely understood. In view of functional involvement of Fas/FasL system in physiological postcanalicular type II cell apoptosis, we speculated this system may also be a critical regulator of hyperoxia-induced apoptosis. The aim of this study was to investigate the effects of hyperoxia on apoptosis and apoptotic gene expression in alveolar epithelial cells. Apoptosis was studied by TUNEL, electron microscopy, DNA size analysis, and caspase assays. Fas/FasL expression was determined by Western blot analysis and RPA. We determined that in MLE-12 cells exposed to hyperoxia, caspase-mediated apoptosis was the first morphologically and biochemically recognizable mode of cell death, followed by necrosis of residual adherent cells. The apoptotic stage was associated with a threefold upregulation of Fas mRNA and protein expression and increased susceptibility to direct Fas receptor activation, concomitant with a threefold increase of FasL protein levels. Fas gene silencing by siRNAs significantly reduced hyperoxia-induced apoptosis. In murine fetal type II cells, hyperoxia similarly induced markedly increased Fas/FasL protein expression, confirming validity of results obtained in transformed MLE-12 cells. Our findings implicate the Fas/FasL system as an important regulator of hyperoxia-induced type II cell apoptosis. Elucidation of regulation of hyperoxia-induced lung apoptosis may lead to alternative therapeutic strategies for perinatal or adult pulmonary diseases characterized by dysregulated type II cell apoptosis.

scholarly journals Fatty acid synthase (FASN) regulates the mitochondrial priming of cancer cells

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Barbara Schroeder ◽  
Travis Vander Steen ◽  
Ingrid Espinoza ◽  
Chandra M. Kurapaty Venkatapoorna ◽  
Zeng Hu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Fatty Acid ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cells ◽  
Fatty Acid Synthase ◽  
Xenograft Model ◽  
Fine Tuning ◽  
Bh3 Mimetic

AbstractInhibitors of the lipogenic enzyme fatty acid synthase (FASN) have attracted much attention in the last decade as potential targeted cancer therapies. However, little is known about the molecular determinants of cancer cell sensitivity to FASN inhibitors (FASNis), which is a major roadblock to their therapeutic application. Here, we find that pharmacological starvation of endogenously produced FAs is a previously unrecognized metabolic stress that heightens mitochondrial apoptotic priming and favors cell death induction by BH3 mimetic inhibitors. Evaluation of the death decision circuits controlled by the BCL-2 family of proteins revealed that FASN inhibition is accompanied by the upregulation of the pro-death BH3-only proteins BIM, PUMA, and NOXA. Cell death triggered by FASN inhibition, which causally involves a palmitate/NADPH-related redox imbalance, is markedly diminished by concurrent loss of BIM or PUMA, suggesting that FASN activity controls cancer cell survival by fine-tuning the BH3 only proteins-dependent mitochondrial threshold for apoptosis. FASN inhibition results in a heightened mitochondrial apoptosis priming, shifting cells toward a primed-for-death state “addicted” to the anti-apoptotic protein BCL-2. Accordingly, co-administration of a FASNi synergistically augments the apoptosis-inducing activity of the dual BCL-XL/BCL-2 inhibitor ABT-263 (navitoclax) and the BCL-2 specific BH3-mimetic ABT-199 (venetoclax). FASN inhibition, however, fails to sensitize breast cancer cells to MCL-1- and BCL-XL-selective inhibitors such as S63845 and A1331852. A human breast cancer xenograft model evidenced that oral administration of the only clinically available FASNi drastically sensitizes FASN-addicted breast tumors to ineffective single-agents navitoclax and venetoclax in vivo. In summary, a novel FASN-driven facet of the mitochondrial priming mechanistically links the redox-buffering mechanism of FASN activity to the intrinsic apoptotic threshold in breast cancer cells. Combining next-generation FASNis with BCL-2-specific BH3 mimetics that directly activate the apoptotic machinery might generate more potent and longer-lasting antitumor responses in a clinical setting.

scholarly journals Advanced microscopic evaluation of parallel type I and type II cell deaths induced by multi-functionalized gold nanocages in breast cancer

2019 ◽  
Vol 1 (3) ◽  
pp. 989-1001 ◽  
Author(s):  
Sreejith Raveendran ◽  
Anindito Sen ◽  
Hiromi Ito-Tanaka ◽  
Kazunori Kato ◽  
Toru Maekawa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Type I ◽  
Type Ii ◽  
Microscopic Evaluation ◽  
Type Ii Cell ◽  
Gold Nanocages ◽  
Parallel Type

This work evaluates the potential of type I and type II cell deaths in parallel killing of breast cancer cells to mitigate the induced chemoresistance caused.

scholarly journals Exposure to Nitric Oxide And Oxygen Causes Rat Alveolar Type II Cell Death 1568

1997 ◽  
Vol 41 ◽  
pp. 264-264
Author(s):  
Anthony J Piazza ◽  
Lou Ann Brown ◽  
Lucky Jain
Keyword(s):  
Nitric Oxide ◽  
Cell Death ◽  
Alveolar Type ◽  
Type Ii ◽  
Alveolar Type Ii Cell ◽  
Type Ii Cell

scholarly journals Endosomal compartment contributes to the propagation of CD95/Fas-mediated signals in type II cells

2008 ◽  
Vol 413 (3) ◽  
pp. 467-478 ◽  
Author(s):  
Paola Matarrese ◽  
Valeria Manganelli ◽  
Tina Garofalo ◽  
Antonella Tinari ◽  
Lucrezia Gambardella ◽  
...  
Keyword(s):  
Cell Death ◽  
Cross Talk ◽  
Fas Ligand ◽  
Type Ii Cells ◽  
Type Ii ◽  
Ligand Interaction ◽  
Directional Movement ◽  
Type Ii Cell ◽  
Endocytic Vesicles

Participation of diverse organelles in the intracellular signalling that follows CD95/Fas receptor ligation encompasses a series of subcellular changes that are mandatory for, or even bolster, the apoptotic cascade. In the present study, we analysed the role of endocytosis in the propagation of cell death signalling after CD95/Fas engagement in type II cells (CEM cells). We show that this receptor–ligand interaction triggers endocytosis independently of any caspase activation. This FasL (Fas ligand)-induced endocytosis also leads to an early and directional ‘movement’ of endocytic vesicles towards the mitochondrial compartment. In turn, this cross-talk between endosomal and mitochondrial compartments was followed by the loss of the mitochondrial membrane potential and apoptosis execution. This cell remodelling was absent in receptor-independent cell death, such as that induced by the mitochondriotropic drug staurosporine, and in a CEM cell line selected for its multidrug resistance (CEM VBL100). In these cells a reduced FasL (Fas ligand)-induced endocytosis and a reduced organelle cross-talk corresponded to a reduced apoptosis. Altogether, these findings suggest a key role of endocytosis in the propagation and amplification of the CD95/Fas-activated signalling leading to type II cell demise.

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