Decreased Intracellular Superoxide Levels Activate Sindbis Virus-induced Apoptosis

Lin, Kuo I.; Pasinelli, Piera; Brown, Robert H.; Hardwick, J. Marie; Ratan, Rajiv R.

doi:10.1074/jbc.274.19.13650

Cited by 35 publications

(18 citation statements)

References 61 publications

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“…These authors attribute these effects to lessened survival signaling by Ras, NF-B, or AP-1 (32-34) as a consequence of reduced ROS con- centrations. This is consistent with the promotion of apoptosis in diverse tumor cell types when ROS levels are reduced (17,(35)(36)(37) and the proposed protective role of ROS generated by NAD(P)H oxidases such as AIF and AIF-M2 in healthy cells. As with AIF-M2, the DNA binding activity of AIF also presents an opportunity to regulate the production of ROS through control of AIF oxidoreductase activity.…”

Section: Discussionsupporting

confidence: 68%

DNA Binding Suppresses Human AIF-M2 Activity and Provides a Connection between Redox Chemistry, Reactive Oxygen Species, and Apoptosis

Gong

Hay

Marshall

et al. 2007

Journal of Biological Chemistry

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Human AIF-M2 is an unusual flavoprotein oxidoreductase that binds DNA, nicotinamide coenzyme, and the modified flavin 6-hydroxy-FAD. Using multiple solution methods to investigate the redox chemistry and binding interactions of AIF-M2, we demonstrate that binding of DNA and coenzyme to AIF-M2 is mutually exclusive. We also show that DNA binding does not perturb the redox chemistry of AIF-M2, but it has significant effects on the reduction kinetics of the 6-hydroxy-FAD cofactor by NAD(P)H. Based on quantitative analysis of ligand binding and redox chemistry, we propose a model for the function of AIF-M2. In this model, DNA binding suppresses the redox activity of AIF-M2 by preventing the binding of the reducing coenzyme NAD(P)H. This DNA-mediated suppression of AIF-M2 activity is expected to lower cellular levels of superoxide and peroxide, thereby lessening survival signaling by Ras, NF-B, or AP-1, as suggested from knock-out studies of the related AIF in human colon cancer cell lines. We show marked differences between AIF-M2 and AIF. DNA and coenzyme binding activity is retained in the C-terminal deletion mutant AIF-M2-(⌬319 -613), whereas DNA binds to the C-terminal D3 domain of AIF. Our work provides the first analysis of AIF-M2 ligand interactions and redox chemistry and identifies an important mechanistic connection between coenzyme and DNA binding, redox activity, and the apoptotic function of AIF-M2. Through its DNA binding activity, we suggest that AIF-M2 lessens survival cell signaling in the presence of foreign (e.g. bacterial and (retro)viral) cytosolic DNA, thus contributing to the onset of apoptosis.Apoptosis (programmed cell death), a cellular process in higher organisms by which cells die (1, 2), can be induced by toxic insult (e.g. chemical damage) or physical disruption of cells. It is critical in the development of multicellular organisms, including the development of the embryo and vital organs, and in cellular homeostasis (3). Up to 70 billion human adult cells undergo apoptosis each day (4). Lesions in the apoptotic process or its regulation result in developmental defects, immortalized cells, and cancers (3). The mitochondrion is a key apoptosis regulator, and pro-apoptotic and cell damage-controlled pathways feed back to the mitochondrion and induce permeabilization of mitochondrial membranes (5). In part, this is under the control of the Bcl-2 protein family, which contains members with either pro-(e.g. Bax) or anti-apoptotic (e.g. Bcl-2) functions (6). Cytotoxic molecules in the mitochondrial intermembrane space are released on membrane permeabilization and act as cell death effectors, some depending on activation by caspase proteases (7). Release of cytochrome c triggers activation of the initiator caspase-9. Downstream activation of other caspases leads to proteolytic cleavage of key target molecules (e.g. laminins) leading to cell morphology changes such as plasma membrane perturbations, condensation and fragmentation of nuclear chromatin, and compaction of cytoplasmic organelles and...

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Section: Discussionsupporting

confidence: 68%

DNA Binding Suppresses Human AIF-M2 Activity and Provides a Connection between Redox Chemistry, Reactive Oxygen Species, and Apoptosis

Gong

Hay

Marshall

et al. 2007

Journal of Biological Chemistry

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“…Although ROS have been conventionally thought to be a cause of stress-induced cell death, ROS may provide tumor cells with survival advantage over normal counterparts (Cerutti, 1985). Furthermore, recent studies suggest a pro-survival role for ROS at the low level in FAS-mediated cell death and Sindbis virus-induced apoptosis (Clement and Stramenkovic, 1996;Lin et al, 1999). In this context, our findings provide further evidence for antiapoptotic activity of ROS and support the view that ROS are important intracellular signaling molecules regulating the balance between survival and cell death.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of NADPH oxidase 4 activates apoptosis via the AKT/apoptosis signal-regulating kinase 1 pathway in pancreatic cancer PANC-1 cells

et al. 2006

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Pancreatic adenocarcinoma is an aggressive human malignancy and is characterized by resistance to apoptosis. Recently, NADPH oxidase (Nox) 4-mediated generation of intracellular reactive oxygen species (ROS) was proposed to confer antiapoptotic activity and thus a growth advantage to pancreatic cancer cells. The signaling mechanism by which Nox4 transmits cell survival signals remains unclear. Here, we show that both a flavoprotein inhibitor, diphenylene iodonium (DPI), and small interfering RNAs designed to target Nox4 mRNA (siNox4R-NAs) inhibited superoxide production in PANC-1 pancreatic cancer cells, and depletion of ROS by DPI or siNox4RNAs induced apoptosis. Parallely, DPI treatment and siNox4RNA transfection blocked activation of the cell survival kinase AKT by attenuating phosphorylation of AKT. Furthermore, AKT phosphorylation of apoptosis signal-regulating kinase 1 (ASK1) on Ser-83 was reduced by DPI and siNox4RNAs. When ASK1Ser83Ala (an AKT phosphorylation-defective ASK1 mutant) was introduced into PANC-1 cells, this mutant alone induced apoptosis. But, addition of DPI or co-transfection of siNox4RNA had no additive effect, indicating that the mutant can substitute for these reagents in apoptosis induction. Taken together, these findings suggest that ROS generated by Nox4, at least in part, transmit cell survival signals through the AKT-ASK1 pathway in pancreatic cancer cells and their depletion leads to apoptosis.

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“…In particular, exogenous H 2 O 2 causes apoptosis at low doses and necrosis at high doses (29). Recent data suggest, however, that ROS inhibit apoptosis in smooth muscle (9), leukemia cells (10), colorectal (11), and prostate cancer cells (12). The prosurvival effect of ROS can be mediated through antiapoptotic redox-sensitive pathways known to be activated by ROS (e.g.…”

mentioning

confidence: 99%

Reactive Oxygen Species Produced by NAD(P)H Oxidase Inhibit Apoptosis in Pancreatic Cancer Cells

Vaquero¹,

Edderkaoui²,

Pandol

et al. 2004

Journal of Biological Chemistry

321

275

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One reason why pancreatic cancer is so aggressive and unresponsive to treatments is its resistance to apoptosis. We report here that reactive oxygen species (ROS) are a prosurvival, antiapoptotic factor in pancreatic cancer cells. Human pancreatic adenocarcinoma MIA PaCa-2 and PANC-1 cells generated ROS, which was stimulated by growth factors (serum, insulin-like growth factor I, or fibroblast growth factor-2). Growth factors also stimulated membrane NAD(P)H oxidase activity in these cells. Both intracellular ROS and NAD(P)H oxidase activity were inhibited by antioxidants tiron and N-acetylcysteine and the inhibitor of flavoprotein-dependent oxidases, diphenylene iodo- Pancreatic adenocarcinoma is an aggressive malignancy resistant to chemotherapy and radiotherapy (1). One mechanism mediating pancreatic cancer aggressiveness and unresponsiveness to treatment is its resistance to apoptosis. Constitutive activation of antiapoptotic proteins such as transcription factors NF-B (2) and signal transducers and activators of transcription (3), heat shock proteins (4), or phosphatidylinositide 3-kinase (5) is thought to contribute to pancreatic cancer resistance to apoptosis. We hypothesized that a key factor mediating this resistance is ROS 1 generated in pancreatic cancer cells. Although ROS have long been thought to promote cell death (6 -8), recent data (9 -12) suggest that they may also play a prosurvival role. ROS can activate the above mentioned antiapoptotic signaling pathways. In this regard, we recently showed (13) (12, 19 -21). Furthermore, functional components of the phagocytic NAD(P)H oxidase have been found to mediate superoxide production in some nonphagocytic cells (22,23). Other ROS-generating enzymes are xanthine oxidase, nitric-oxide synthase (NOS), phospholipase A 2 (PLA 2 ), and lipoxygenases (14). A growing body of evidence indicates that ROS play signaling roles in physiologic and pathophysiologic processes, including proliferation (24), adhesion (25), and hypertension (17, 26). In particular, growth factors are known to stimulate ROS in a variety of cell types through receptor-transducing pathways,

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Decreased Intracellular Superoxide Levels Activate Sindbis Virus-induced Apoptosis

Abstract: Infection of many cultured cell types with Sindbis virus (SV), an alphavirus, triggers apoptosis through

Cited by 35 publications

References 61 publications

DNA Binding Suppresses Human AIF-M2 Activity and Provides a Connection between Redox Chemistry, Reactive Oxygen Species, and Apoptosis

DNA Binding Suppresses Human AIF-M2 Activity and Provides a Connection between Redox Chemistry, Reactive Oxygen Species, and Apoptosis

Inhibition of NADPH oxidase 4 activates apoptosis via the AKT/apoptosis signal-regulating kinase 1 pathway in pancreatic cancer PANC-1 cells

Reactive Oxygen Species Produced by NAD(P)H Oxidase Inhibit Apoptosis in Pancreatic Cancer Cells

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