Mitochondrial reactive oxygen species in cell death signaling

Fleury, Christophe; Mignotte, Bernard; Vayssière, Jean-Luc

doi:10.1016/s0300-9084(02)01369-x

Cited by 921 publications

(621 citation statements)

References 113 publications

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“…Our results are, thus, in line with these observations. Oxidative stress may be involved in mediating apoptosis at early and/or late stages through different possible mechanisms (Fleury et al, 2002). Oxidative stress may trigger or mediate apoptosis by causing DNA damage, activation of apoptotic signaling pathways (such as MAP kinases and p53), induction of mitochondrial permeability transition, the release of mitochondrial death amplification factors, as well as activation of intracellular caspases (Datta et al, 2000;Kim and Park, 2003;Le Bras et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Diepoxybutane activates the mitochondrial apoptotic pathway and mediates apoptosis in human lymphoblasts through oxidative stress

Yadavilli¹,

Martinez‐Ceballos²,

Snowden-Aikens³

et al. 2007

Toxicology in Vitro

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Diepoxybutane (DEB) is the most potent metabolite of the environmental chemical 1, 3-butadiene (BD), which is prevalent in petrochemical industrial areas. BD is a known mutagen and human carcinogen, and possesses multi-systems organ toxicity. We recently reported that DEB-induced cell death in TK6 lymphoblasts was due to the occurrence of apoptosis, and not necrosis. In this study, we investigated the molecular mechanisms responsible for DEB-induced apoptosis in these cells. Bax and Bak were found to be over-expressed and activated, and the mitochondrial trans-membrane potential was attenuated in cells undergoing DEB-induced apoptosis. Cytochrome c was depleted from the mitochondria of TK6 cells undergoing apoptosis, and was released into the cytosol in Jurkat-T lymphoblasts exposed to the same concentrations of DEB. Executioner caspase 3 was deduced to be activated by initiator caspase 9. DEB induced reactive oxygen species (ROS) formation, and the ROS scavenger N-acetyl-L-cysteine effectively blocked DEB-induced apoptosis in TK6 cells.Collectively, these results demonstrate that the mitochondrial apoptotic pathway is activated to mediate DEB-induced apoptosis in human TK6 lymphoblasts. These results further demonstrate that DEB-induced apoptosis is also mediated by the DEB-induced generation of ROS. This is the first report to examine the mechanism of DEB-induced apoptosis in human lymphoblasts.

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Section: Discussionmentioning

confidence: 99%

Diepoxybutane activates the mitochondrial apoptotic pathway and mediates apoptosis in human lymphoblasts through oxidative stress

Yadavilli¹,

Martinez‐Ceballos²,

Snowden-Aikens³

et al. 2007

Toxicology in Vitro

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“…ROS formation came mainly from the mitochondria and NADPH oxidase. Bcl-2, in addition to its role to maintain permeability of outer mitochondrial membrane, might act as an anti-oxidant partner to block a putative ROS-mediated step in the cascade of apoptosis (36). Overexpression of Bcl-2 shifted the cellular redox potential to a more reduced state (37).…”

Section: Inhibition Of Tumor Cellmentioning

confidence: 99%

2′-Benzoyloxycinnamaldehyde Induces Apoptosis in Human Carcinoma via Reactive Oxygen Species

Han

Lee

Shin

et al. 2004

Journal of Biological Chemistry

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2 -Hydroxycinnamaldehyde (HCA) has been shown to have inhibitory effects on farnesyl protein transferase in vitro, angiogenesis, and tumor cell growth. However, mechanism for these inhibitions remains unknown. As a derivative of HCA, BCA (2 -benzoyl-oxycinnamaldehyde) was synthesized by replacing hydroxyl group with benzoyl-oxyl group. When p53-mutated cancer cell lines (MDA-MB-231 breast cancer cell and SW620 colon cancer cell) were treated with 10 M HCA or BCA, it induced growth arrest and apoptosis of tumor cells. Markers of apoptosis such as degradations of chromosomal DNA and poly(ADP-ribose) polymerase and activation of caspase-3 were detected after HCA or BCA treatment. BCA-induced apoptosis was blocked by pretreatment of cells with anti-oxidants, glutathione, or N-acetyl-cysteine. In addition, BCA-induced activation of caspase-3 and degradation of poly(ADP-ribose) polymerase were abolished by pretreatment of cells with the anti-oxidants. These results suggest that reactive oxygen species are major regulator of BCA-induced apoptosis. HCA or BCA-induced accumulation of reactive oxygen species was detected by using DCF-DA, an intracellular probe of oxidative stress. Furthermore, when BCA (100 mg/kg) was administrated intraperitoneally or orally into a nude mouse, it inhibited >88 or 41% of tumor growth, respectively, without any detectable weight change. These results suggest that BCA is a good drug candidate for cancer therapy.

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“…18 Reactive oxygen may also play some role in degradation of mutant P53, since there is often a massive production of reactive oxygen species during the late phase of the apoptotic process (for a review see Ref. 19), which occurred in 70.4 cells at the 24 hr time point post-irradiation. It remains unclear, however, why there was no comparable effect in UV-exposed 55.1c cells where the wild-type form of the P53 protein was still present at high levels 24 hr after irradiation of cells, in particular, since MDM2, which initiates degradation of P53, was increased in 55.1c cells following UV-irradiation while it remained unchanged in UV-exposed p53 defective cells.…”

Section: Discussionmentioning

confidence: 99%

Regulation of P53 stability in p53 mutated human and mouse hepatoma cells

Hailfinger

Jaworski

Marx‐Stoelting

et al. 2007

Intl Journal of Cancer

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The tumor suppressor p53 is frequently mutated in cancer. We have investigated the regulation of P53 in p53 wild type mouse hepatoma cells (line 55.1c), in p53 heterozygeously mutated cells (56.1b) and in p53 defective cells (lines 56.1d, 70.4 and HUH7) under various experimental settings. The basal levels of P53 were low in 55.1c cells, but nuclear accumulation occurred upon UVirradiation. Similarly, UV-exposure induced stabilization of P53 in the heterozygeously p53 mutated 56.1b hepatoma cells. By contrast, the 3 hepatoma lines, which lack transcriptionally active P53, demonstrated high basal nuclear concentrations of P53 protein and, unexpectedly, showed loss of P53 upon UV-irradiation. Expression of p53 mRNA was also decreased in p53 defective cells after 24 hr post UV-irradiation, which may be linked to induction of apoptosis of the irradiated cells under these conditions. Other stressors like H 2 O 2 also mediated a decrease in P53 concentration in p53 defective cells. This effect occurred at very low concentrations and was already detectable 1-2 hr after exposure of cells. There were no signs of apoptosis of H 2 O 2 -exposed cells at this time point and no significant changes in p53 mRNA or MDM2 level. These unexpected findings indicate a new aspect related to regulation of P53 stability in cells with a defect in the tumor suppressor protein. ' 2007 Wiley-Liss, Inc.Key words: p53 mutation; hepatoma cells; MDM2; DFX; UV irradiation; ROS The p53 tumor suppressor protein is a powerful cellular caretaker, which protects cells from malignant transformation by means of transcriptional upregulation of proapoptotic, DNA repair and cell cycle arrest related proteins. In unstressed cells the P53 level is kept low by the E3 ubiquitin ligase MDM2, which transfers activated ubiquitin residues to P53. 1 Polyubiquitination of P53 leads to a rapid proteasomal degradation of the tumor suppressor, preventing P53 from affecting the cells' viability. P53 itself transcriptionally upregulates MDM2 expression, forming a negative feedback loop.Stress signals, caused by UV-light, DNA-damaging agents or hypoxia lead to an activation of several kinases, of which the most prominent members are the ATM (ataxia-telangiectasia mutated), ATR (ataxia-telangiectasia and Rad3-related), DNA-dependent protein kinase and casein kinase II, which phosphorylate the P53 protein at different sites (for review see Ref.2). Polyphosphorylation at the N-terminus of P53 reduces MDM2-dependent degradation, leading to an accumulation of the P53 protein in the cell followed by upregulation of apoptosis or cell cycle arrest related proteins. Exposure of cells to UV light correlates with post-translational modifications of P53, such as phosphorylation of serine 15 (mouse serine 18) and serine 20 (mouse serine 23). Desferrioxamine (DFX) treatment, which mimics hypoxia, results in phosphorylation of serine 15. Both sites are known to reduce MDM2-binding when phosphorylated. 3

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Mitochondrial reactive oxygen species in cell death signaling

Cited by 921 publications

References 113 publications

Diepoxybutane activates the mitochondrial apoptotic pathway and mediates apoptosis in human lymphoblasts through oxidative stress

Diepoxybutane activates the mitochondrial apoptotic pathway and mediates apoptosis in human lymphoblasts through oxidative stress

2′-Benzoyloxycinnamaldehyde Induces Apoptosis in Human Carcinoma via Reactive Oxygen Species

Regulation of P53 stability in p53 mutated human and mouse hepatoma cells

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