Epidermal Growth Factor Receptor-dependent Akt Activation by Oxidative Stress Enhances Cell Survival

Wang, Xiantao; McCullough, Karen D.; Franke, Thomas; Holbrook, Nikki J.

doi:10.1074/jbc.275.19.14624

Cited by 414 publications

(365 citation statements)

References 49 publications

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“…We therefore propose that Nox4-dependent cell survival signaling is mediated by the AKT-ASK1 kinase cascade, and that antagonizing this signaling pathway by DPI or siNox4RNAs results in activation of apoptosis. Similarly, the anticancer drug paclitaxelinduced apoptosis of ovarian cancer cells is mediated by negative regulation of AKT-ASK1 phosphorylation signaling (Mabuchi et al, 2004) and AKT activation by H 2 O 2 confers protection against apoptosis (Wang et al, 2000). It has been reported that ROS oxidize thioredoxin (TRX), a negative regulator of ASK1, and thereby dissociate TRX from pre-existing TRX-ASK1 complexes, resulting in the activation of ASK1 and the subsequent ASK1-dependent apoptosis (Saitoh et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…Alternative potential targets for ROS are the protein kinases. Angiotensin-or EGF-induced AKT activation has been reported to be mediated by ROS including H 2 O 2 , suggesting that AKT is redox sensitive (Ushio-Fukai et al, 1999;Wang et al, 2000). In addition, PtdIns(3,4,5)P 3 binding to AKT translocates AKT to the plasma membrane, resulting in AKT activation through its phosphorylation by the kinases such as phosphatidylinositol-dependent kinase-1 (PDK1) and -2 (PDK2) (Alessi et al, 1997: Alessi andCohen, 1998).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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“…Based on our in vitro data, it is thought that this superior migratory response of EGFR-MSC over primary MSCs in vivo resulted from several biological events that were induced by EGFR gene insertion: (1) direct enhancement of migration by interaction of EGFR and its ligands as demonstrated in vitro; (2) resistance to FasL-induced apoptosis, because FasL is known to be expressed in both normal and neoplastic CNS tissues, 44 Glioma gene therapy with EGFR-transfected MSCs H Sato et al mechanisms including activation of PI3-K. 45 Akt provides a powerful survival signal in many systems, 46 and a recent study has demonstrated that Akt-engineered MSCs are more resistant to apoptosis and can enhance cardiac repair after transplantation into the ischemic rat heart. 47 Indeed, both bulk and cloned EGFR-MSCs were maintained as a cell line over 30 passages, whereas primary MSCs died after three to four passages within a span of a month after their harvesting from bone marrow.…”

Section: Discussionmentioning

confidence: 99%

Epidermal growth factor receptor-transfected bone marrow stromal cells exhibit enhanced migratory response and therapeutic potential against murine brain tumors

et al. 2005

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We have created a novel cellular vehicle for gene therapy of malignant gliomas by transfection of murine bone marrow stroma cells (MSCs) with a cDNA encoding epidermal growth factor receptor (EGFR). These cells (EGFR-MSCs) demonstrate enhanced migratory responses toward glioma-conditioned media in comparison to primary MSCs in vitro. Enhanced migration of EGFR-MSC was at least partially dependent on EGF-EGFR, PI3-, MAP kinase kinase, and MAP kinases, protein kinase C, and actin polymerization. Unlike primary MSCs, EGFR-MSCs were resistant to FasL-mediated cytotoxicity and were capable of stimulating allogeneic mixed lymphocyte reaction, suggesting EGFR-MSCs possess suitable characteristics as vehicles for brain tumor immuno-gene therapy. Following injection at various sites, including the contralateral hemisphere in the brain of syngeneic mice, EGFR-MSCs were able to migrate toward GL261 gliomas or B16 melanoma in vivo. Finally, intratumoral injection with EGFR-MSC adenovirally engineered to secrete interferon-a to intracranial GL261 resulted in significantly prolonged survival in comparison to controls. These data indicate that EGFR-MSCs may serve as attractive vehicles for infiltrating brain malignancies such as malignant gliomas.

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“…Several studies have reported that environmental stresses capable of inducing apoptosis, such as UVC, ionizing radiation (IR), and hyperosmotic stress lead to the downregulation of the PI3K/Akt pathway (Meier et al, 1998;Zhou et al, 1998;Zundel and Giaccia, 1998), and it has been suggested that such downregulation is important in the apoptotic process. However, Akt is activated in response to oxidant injury as well as several other stresses known to exert their cytotoxic effects in part through generation of ROS or perturbations in cellular redox status (Konishi et al, 1997;Sonoda et al, 1999;Klotz et al, 2000;Wang et al, 2000b;Huang et al, 2001).…”

Section: Pi3-kinase/akt Pathwaymentioning

confidence: 99%

Cellular response to oxidative stress: Signaling for suicide and survival*

Martindale

Holbrook

2002

Journal Cellular Physiology

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2,094

1,596

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Reactive oxygen species (ROS), whether produced endogenously as a consequence of normal cell functions or derived from external sources, pose a constant threat to cells living in an aerobic environment as they can result in severe damage to DNA, protein, and lipids. The importance of oxidative damage to the pathogenesis of many diseases as well as to degenerative processes of aging has becoming increasingly apparent over the past few years. Cells contain a number of antioxidant defenses to minimize fluctuations in ROS, but ROS generation often exceeds the cell's antioxidant capacity, resulting in a condition termed oxidative stress. Host survival depends upon the ability of cells and tissues to adapt to or resist the stress, and repair or remove damaged molecules or cells. Numerous stress response mechanisms have evolved for these purposes, and they are rapidly activated in response to oxidative insults. Some of the pathways are preferentially linked to enhanced survival, while others are more frequently associated with cell death. Still others have been implicated in both extremes depending on the particular circumstances. In this review, we discuss the various signaling pathways known to be activated in response to oxidative stress in mammalian cells, the mechanisms leading to their activation, and their roles in influencing cell survival. These pathways constitute important avenues for therapeutic interventions aimed at limiting oxidative damage or attenuating its sequelae. Published 2002 Wiley‐Liss, Inc.

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Epidermal Growth Factor Receptor-dependent Akt Activation by Oxidative Stress Enhances Cell Survival

Cited by 414 publications

References 49 publications

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

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

Epidermal growth factor receptor-transfected bone marrow stromal cells exhibit enhanced migratory response and therapeutic potential against murine brain tumors

Cellular response to oxidative stress: Signaling for suicide and survival*

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