scholarly journals Ferroptosis in Lung Cancer: From Molecular Mechanisms to Prognostic and Therapeutic Opportunities

2021 ◽  
Vol 11 ◽  
Author(s):  
Peyman Tabnak ◽  
Zanyar HajiEsmailPoor ◽  
Soroush Soraneh
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Molecular Mechanisms ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Radical Oxygen Species ◽  
Future Studies ◽  
New Horizons ◽  
The Road ◽  
Promising Strategy

Lung cancer is the second commonly diagnosed malignancy worldwide and has the highest mortality rate among all cancers. Tremendous efforts have been made to develop novel strategies against lung cancer; however, the overall survival of patients still is low. Uncovering underlying molecular mechanisms of this disease can open up new horizons for its treatment. Ferroptosis is a newly discovered type of programmed cell death that, in an iron-dependent manner, peroxidizes unsaturated phospholipids and results in the accumulation of radical oxygen species. Subsequent oxidative damage caused by ferroptosis contributes to cell death in tumor cells. Therefore, understanding its molecular mechanisms in lung cancer appears as a promising strategy to induce ferroptosis selectively. According to evidence published up to now, significant numbers of research have been done to identify ferroptosis regulators in lung cancer. Therefore, this review aims to provide a comprehensive standpoint of molecular mechanisms of ferroptosis in lung cancer and address these molecules’ prognostic and therapeutic values, hoping that the road for future studies in this field will be paved more efficiently.

The molecular mechanisms of Phytophthora infestans in response to reactive oxygen species (ROS) stress

2021 ◽  
Author(s):  
Xiumei Luo ◽  
Tingting Tian ◽  
Maxime Bonnave ◽  
Xue Tan ◽  
Xiaoqing Huang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Late Blight ◽  
Phytophthora Infestans ◽  
Molecular Mechanisms ◽  
Reactive Oxygen ◽  
Microbial Pathogens ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Tor Signaling ◽  
Potato Resistance

Reactive oxygen species (ROS) are critical for the growth, development, proliferation, and pathogenicity of microbial pathogens; however, excessive levels of ROS are toxic. Little is known regarding the signaling cascades in response to ROS stress in oomycetes such as Phytophthora infestans, the causal agent of potato late blight. Here, P. infestans was used as a model system to investigate the mechanism underlying the response to ROS stress in oomycete pathogens. Results showed severe defects in sporangium germination, mycelial growth, appressorium formation, and virulence of P. infestans in response to H2O2 stress. Importantly, these phenotypes mimic those of P. infestans treated with rapamycin, the inhibitor of target of rapamycin (TOR, 1-phosphatidylinositol-3-kinase). Strong synergism occurred when P. infestans was treated with a combination of H2O2 and rapamycin, suggesting that a crosstalk exists between ROS stress and the TOR signaling pathway. Comprehensive analysis of transcriptome, proteome and phosphorylation omics showed that H2O2 stress significantly induced the operation of the TOR-mediated autophagy pathway. Monodansylcadaverine (MDC) staining showed that in the presence of H2O2 and rapamycin, the autophagosome level increased in a dosage-dependent manner. Furthermore, transgenic potatoes containing double-stranded RNA of PiTOR (TOR in P. infestans) displayed high resistance to P. infestans. Taken together, TOR is involved in the ROS response and is a potential target for control of oomycete diseases, as host-mediated silencing of PiTOR enhances potato resistance to late blight.

Involvement of Caspases in Neutrophil Apoptosis: Regulation by Reactive Oxygen Species

Blood ◽  
1998 ◽  
Vol 92 (12) ◽  
pp. 4808-4818 ◽  
Author(s):  
Bengt Fadeel ◽  
Anders Åhlin ◽  
Jan-Inge Henter ◽  
Sten Orrenius ◽  
Mark B. Hampton
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Nadph Oxidase ◽  
Reactive Oxygen ◽  
Human Neutrophils ◽  
Neutrophil Apoptosis ◽  
Dependent Manner ◽  
Caspase Activity ◽  
Oxygen Species ◽  
Spontaneous Apoptosis

Abstract Human neutrophils have a short half-life and are believed to die by apoptosis or programmed cell death both in vivo and in vitro. We found that caspases are activated in a time-dependent manner in neutrophils undergoing spontaneous apoptosis, concomitant with other characteristic features of apoptotic cell death such as morphologic changes, phosphatidylserine (PS) exposure, and DNA fragmentation. The treatment of neutrophils with agonistic anti-Fas monoclonal antibodies (MoAbs) significantly accelerated this process. However, in cells treated with the potent neutrophil activator phorbol 12-myristate 13-acetate (PMA), caspase activity was only evident after pharmacologic inhibition of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Similarily, inhibition of the NADPH oxidase in constitutive and Fas/APO-1–triggered apoptosis resulted in increased rather than suppressed levels of caspase activity, suggesting that reactive oxygen species may prevent caspases from functioning optimally in these cells. Moreover, oxidants generated via the NADPH oxidase were essential for PS exposure during PMA-induced cell death, but not for neutrophils undergoing spontaneous apoptosis. We conclude that caspases are an important component of constitutive and Fas/APO-1–triggered neutrophil apoptosis. However, these redox sensitive enzymes are suppressed in activated neutrophils, and an alternate oxidant-dependent pathway is used to mediate PS exposure and neutrophil clearance under these conditions.

MG132 as a proteasome inhibitor induces cell growth inhibition and cell death in A549 lung cancer cells via influencing reactive oxygen species and GSH level

2010 ◽  
Vol 29 (7) ◽  
pp. 607-614 ◽  
Author(s):  
Yong Hwan Han ◽  
Woo Hyun Park
Keyword(s):  
Lung Cancer ◽  
Reactive Oxygen Species ◽  
Cell Cycle ◽  
Cell Death ◽  
Cancer Cells ◽  
Proteasome Inhibitor ◽  
A549 Cells ◽  
Lung Cancer Cells ◽  
Oxygen Species ◽  
A549 Lung

Carbobenzoxy-Leu-Leu-leucinal (MG132) as a proteasome inhibitor has been shown to induce apoptotic cell death through formation of reactive oxygen species (ROS). In the present study, we evaluated the effects of MG132 on the growth of A549 lung cancer cells in relation to cell growth, ROS and glutathione (GSH) levels. Treatment with MG132 inhibited the growth of A549 cells with an IC50 of approximately 20 μM at 24 hours. DNA flow cytometric analysis indicated that 0.5 ∼ 30 μM MG132 induced a G1 phase arrest of the cell cycle in A549 cells. Treatment with 10 or 30 μM MG132 also induced apoptosis, as evidenced by sub-G1 cells and annexin V staining cells. This was accompanied by the loss of mitochondrial membrane potential (MMP; Δψm). The intracellular ROS levels including O2•- were strongly increased in 10 or 30 μM MG132-treated A549 cells but were down-regulated in 0.1, 0.5 or 1 μM MG132-treated cells. Furthermore, 10 or 30 μM MG132 increased mitochondrial O2•- level but 0.1, 0.5 or 1 μM MG132 decreased that. In addition, 10 or 30 μM MG132 induced GSH depletion in A549 cells. In conclusion, MG132 inhibited the growth of human A549 cells via inducing the cell cycle arrest as well as triggering apoptosis, which was in part correlated with the changes of ROS and GSH levels. Our present data provide important information on the anti-growth mechanisms of MG132 in A549 lung cancer cells in relation to ROS and GSH.

scholarly journals The Pyridone-Annelated Isoindigo (5‘-Cl) Induces Apoptosis, Dysregulation of Mitochondria and Formation of ROS in Leukemic HL-60 Cells

2015 ◽  
Vol 35 (5) ◽  
pp. 1958-1974 ◽  
Author(s):  
Ayman M. Saleh ◽  
Ahmad Aljada ◽  
Mustafa M. El-Abadelah ◽  
Salim S. Sabri ◽  
Jalal A. Zahra ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Molecular Mechanisms ◽  
Reactive Oxygen ◽  
Pyrrolidine Dithiocarbamate ◽  
Nuclear Staining ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Mitochondrial Functions ◽  
Apoptotic Activity ◽  
Induced Apoptosis

Background/Aims: In our quest to develop an isoindigo with improved efficacy and bioavailability, we recently synthesized a series of novel substituted pyridone-annelated isoindigo and evaluated their antiproliferative effects. We identified the compound [(E)-1-(5'-Chloro-2'-oxoindolin-3'-ylidene)-6-ethyl-2,3,6,9-tetrahydro-2,9-dioxo-1H-pyrrolo[3,2-f] quinoline-8-carboxylic acid], abbreviated as 5'-Cl, which shows selective antiproliferative activities against various cancer cell lines mediated through apoptosis. Here we have investigated the molecular mechanisms underlying the apoptotic activity of 5'-Cl in the human promyelocytic leukemia HL-60 cells. Methods: We employed different methods to determine the apoptotic pathways triggered by 5'-Cl in HL-60 cells, using flow cytometry, nuclear staining, caspases activation, mitochondria functioning, generation of reactive oxygen species (ROS) and Western blotting techniques. Results: Low concentrations (1-8 µM) of 5'-Cl inhibited the growth of HL-60 cells in a dose and time-dependent manner. Cytotoxicity of this compound is found to be mediated by a caspase-dependent apoptosis. Also, there were indications of caspase independent apoptosis as z-VAD-FMK failed to fully rescue the cells from 5‘-Cl-induced apoptosis. In addition, the compound triggered generation of Reactive Oxygen Species (ROS), caused depolarization of the mitochondrial inner membrane, decreased the level of cellular ATP, modulated the expression and phosphorylation of Bcl-2 leading to loss of its association with Bax and increased the release of cytochrome c to the cytosol of treated cells. The effects of 5‘-Cl on mitochondria and apoptosis were substantially blocked in the presence of a combination between z-VAD-FMK and either of the ROS scavenger N-acetyl-L-cysteine (NAC) or pyrrolidine dithiocarbamate (PDTC). Conclusion: We demonstrated that the growth inhibitory effects of 5'-Cl in HL-60 cells involve multiple pathways of apoptosis and dysregulation of mitochondrial functions.

scholarly journals α-Synuclein binds and sequesters PIKE-L into Lewy bodies, triggering dopaminergic cell death via AMPK hyperactivation

2017 ◽  
Vol 114 (5) ◽  
pp. 1183-1188 ◽  
Author(s):  
Seong Su Kang ◽  
Zhentao Zhang ◽  
Xia Liu ◽  
Fredric P. Manfredsson ◽  
Li He ◽  
...  
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Lewy Bodies ◽  
Cell Loss ◽  
Dominant Negative ◽  
Dependent Manner ◽  
Ph Domain ◽  
Dopaminergic Cell ◽  
Neuroprotective Actions

The abnormal aggregation of fibrillar α-synuclein in Lewy bodies plays a critical role in the pathogenesis of Parkinson’s disease. However, the molecular mechanisms regulating α-synuclein pathological effects are incompletely understood. Here we show that α-synuclein binds phosphoinositide-3 kinase enhancer L (PIKE-L) in a phosphorylation-dependent manner and sequesters it in Lewy bodies, leading to dopaminergic cell death via AMP-activated protein kinase (AMPK) hyperactivation. α-Synuclein interacts with PIKE-L, an AMPK inhibitory binding partner, and this action is increased by S129 phosphorylation through AMPK and is decreased by Y125 phosphorylation via Src family kinase Fyn. A pleckstrin homology (PH) domain in PIKE-L directly binds α-synuclein and antagonizes its aggregation. Accordingly, PIKE-L overexpression decreases dopaminergic cell death elicited by 1-methyl-4-phenylpyridinium (MPP+), whereas PIKE-L knockdown elevates α-synuclein oligomerization and cell death. The overexpression of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or α-synuclein induces greater dopaminergic cell loss and more severe motor defects in PIKE-KO and Fyn-KO mice than in wild-type mice, and these effects are attenuated by the expression of dominant-negative AMPK. Hence, our findings demonstrate that α-synuclein neutralizes PIKE-L’s neuroprotective actions in synucleinopathies, triggering dopaminergic neuronal death by hyperactivating AMPK.

scholarly journals Rewiring Glucose Metabolism Improves 5-FU Efficacy in Glycolytic p53-Deficient Colorectal Tumors

2021 ◽  
Author(s):  
Marlies Ludikhuize ◽  
Sira Gevers ◽  
Nguyen Nguyen ◽  
Maaike Meerlo ◽  
S. Khadijeh Shafiei Roudbari ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Glucose Metabolism ◽  
Molecular Mechanisms ◽  
Genetically Engineered ◽  
Driver Mutations ◽  
Cycle Arrest ◽  
Promising Strategy ◽  
Clinical Models ◽  
The Warburg Effect

Abstract 5-fluorouracil (5-FU) is the backbone for chemotherapy in colorectal cancer (CRC), however response rates in patients are limited to 50%. Unexpectedly, the molecular mechanisms by which 5-FU ultimately induces toxicity remain debated, limiting the development of strategies to improve its efficacy. How fundamental aspects of cancer, such as driver mutations and phenotypic intra-tumor heterogeneity, relate to the 5-FU response are ill-defined. This is largely due to a shortage of mechanistic studies in pre-clinical models able to recapitulate the key-features of CRC. Here, we analyzed the 5-FU response in human organoids genetically engineered to reproduce the different stages of CRC progression. We find that 5-FU induces pyrimidine imbalance, which leads to DNA damage and cell death. Actively proliferating cancer (stem) cells are, accordingly, efficiently targeted by 5-FU. Importantly, p53 behaves as a discriminating factor for 5-FU sensitivity, whereas p53-deficiency leads to DNA damage-induced cell death, active p53 protects from these effects through inducing cell cycle arrest. Moreover, we find that targeting the Warburg effect, by rewiring glucose metabolism, enhances 5-FU toxicity by altering the nucleotide pool and without increasing toxicity in non-transformed cells. Thus, rewiring glucose metabolism in combination with replication stress-inducing chemotherapies emerges as a promising strategy for CRC treatment.

scholarly journals Is Ferroptosis a Key Component of the Process Leading to Multiorgan Damage in COVID-19?

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1677
Author(s):  
Anna Maria Fratta Pasini ◽  
Chiara Stranieri ◽  
Domenico Girelli ◽  
Fabiana Busti ◽  
Luciano Cominacini
Keyword(s):  
Reactive Oxygen Species ◽  
Fatty Acids ◽  
Cell Death ◽  
Cardiogenic Shock ◽  
Molecular Mechanisms ◽  
Lipid Peroxides ◽  
Oxygen Species ◽  
Intracellular Iron ◽  
Multiple Organs ◽  
Respiratory Pathology

Even though COVID-19 is mostly well-known for affecting respiratory pathology, it can also result in several extrapulmonary manifestations, leading to multiorgan damage. A recent reported case of SARS-CoV-2 myocarditis with cardiogenic shock showed a signature of myocardial and kidney ferroptosis, a novel, iron-dependent programmed cell death. The term ferroptosis was coined in the last decade to describe the form of cell death induced by the small molecule erastin. As a specific inducer of ferroptosis, erastin inhibits cystine-glutamate antiporter system Xc-, blocking transportation into the cytoplasm of cystine, a precursor of glutathione (GSH) in exchange with glutamate and the consequent malfunction of GPX4. Ferroptosis is also promoted by intracellular iron overload and by the iron-dependent accumulation of polyunsaturated fatty acids (PUFA)-derived lipid peroxides. Since depletion of GSH, inactivation of GPX4, altered iron metabolism, and upregulation of PUFA peroxidation by reactive oxygen species are peculiar signs of COVID-19, there is the possibility that SARS-CoV-2 may trigger ferroptosis in the cells of multiple organs, thus contributing to multiorgan damage. Here, we review the molecular mechanisms of ferroptosis and its possible relationship with SARS-CoV-2 infection and multiorgan damage. Finally, we analyze the potential interventions that may combat ferroptosis and, therefore, reduce multiorgan damage.

scholarly journals Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Mariachiara Buccarelli ◽  
Quintino Giorgio D’Alessandris ◽  
Paola Matarrese ◽  
Cristiana Mollinari ◽  
Michele Signore ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Cell Death ◽  
Molecular Mechanisms ◽  
Reactive Oxygen ◽  
Strong Increase ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species

Abstract Background Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults, characterized by a poor prognosis mainly due to recurrence and therapeutic resistance. It has been widely demonstrated that glioblastoma stem-like cells (GSCs), a subpopulation of tumor cells endowed with stem-like properties is responsible for tumor maintenance and progression. Moreover, it has been demonstrated that GSCs contribute to GBM-associated neovascularization processes, through different mechanisms including the transdifferentiation into GSC-derived endothelial cells (GdECs). Methods In order to identify druggable cancer-related pathways in GBM, we assessed the effect of a selection of 349 compounds on both GSCs and GdECs and we selected elesclomol (STA-4783) as the most effective agent in inducing cell death on both GSC and GdEC lines tested. Results Elesclomol has been already described to be a potent oxidative stress inducer. In depth investigation of the molecular mechanisms underlying GSC and GdEC response to elesclomol, confirmed that this compound induces a strong increase in mitochondrial reactive oxygen species (ROS) in both GSCs and GdECs ultimately leading to a non-apoptotic copper-dependent cell death. Moreover, combined in vitro treatment with elesclomol and the alkylating agent temozolomide (TMZ) enhanced the cytotoxicity compared to TMZ alone. Finally, we used our experimental model of mouse brain xenografts to test the combination of elesclomol and TMZ and confirmed their efficacy in vivo. Conclusions Our results support further evaluation of therapeutics targeting oxidative stress such as elesclomol with the aim of satisfying the high unmet medical need in the management of GBM.

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