H2O2 mediates oxidative stress-induced epidermal growth factor receptor phosphorylation

Meves, Alexander; Stock, Sibylle N.; Beyerle, Astrid; Pittelkow, Mark R.; Péus, Dominik

doi:10.1016/s0378-4274(01)00359-9

Cited by 58 publications

(38 citation statements)

References 37 publications

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“…However, clinical studies using antioxidants as an adjuvant to chemotherapy have so far been unsuccessful (10,19,25,28,33,34). L-ascorbic acid may function as either a pro-oxidant or an antioxidant at physiological micromolar concentrations (normal range, <0.1 mM) in the presence of trace amounts of transition metals including copper and iron (20,(34)(35)(36)(37)(38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

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The enhanced tumor inhibitory effects of gefitinib and L-ascorbic acid combination therapy in non-small cell lung cancer cells

et al. 2017

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Abstract. Despite documentation of successful therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with lung cancer, the response rate of patients treated with this therapy remains low. The present study investigated whether L-ascorbic acid serves an adjuvant role in vitro when combined with the EGFR tyrosine kinase inhibitor gefitinib (Iressa ® ) in lung cancer cell lines. A total of three human lung cancer cell lines were used. The antiproliferative effects and changes in the cell cycle and expression of intracellular signaling molecules, including extracellular signal-regulated kinases (Erk), signal transducer and activator of transcription 3 (Stat3) and protein kinase B (Akt), were measured in cells treated with gefitinib and/or L-ascorbic acid at various concentrations. When combined with gefitinib, L-ascorbic acid exhibited an additive effect on cell proliferation in all gefitinib-sensitive and gefitinib-resistant cell lines. A decrement of ~40% was observed with a low dose 0.5 mM L-ascorbic acid and gefitinib in the relatively gefitinib-resistant A549 cell line (85.6±5.4% with gefitinib alone vs. 52.7±7.3% with combination therapy; P=0.046). The downregulation of intracellular signaling cascades, including EGFR, Akt, Erk and Stat3, was also observed. L-Ascorbic acid serves an adjuvant role when administered in combination with gefitinib; however, the degree of inhibition of cell proliferation differs between lung cancer cell lines.

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Section: Discussionmentioning

confidence: 99%

“…Previous studies have revealed that oxidative stress increases phosphorylation of the EGFR in keratinocytes (19)(20)(21). The antioxidant activity of L-ascorbic acid (vitamin C, water-soluble L-ascorbic acid) is achieved primarily via its ability to donate electrons and therefore function as a reducing agent (22).…”

Section: Introductionmentioning

confidence: 99%

The enhanced tumor inhibitory effects of gefitinib and L-ascorbic acid combination therapy in non-small cell lung cancer cells

et al. 2017

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“…EGF/ EGFR pathway has a strong stimulatory effect on hepatoma growth and is frequently overexpressed in human HCC, particular at the more aggressive stage (35). Although the mechanisms underlying increased EGFR signaling may differ, EGFR up-regulation in c-Met-deficient tumors might be caused by increased ROS production (42,43).…”

Section: Discussionmentioning

confidence: 99%

Loss of Hepatocyte Growth Factor/c-Met Signaling Pathway Accelerates Early Stages of N-nitrosodiethylamine–Induced Hepatocarcinogenesis

et al. 2007

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Hepatocyte growth factor (HGF) has been reported to have both positive and negative effects on carcinogenesis. Here, we show that the loss of c-Met signaling in hepatocytes enhanced rather than suppressed the early stages of chemical hepatocarcinogenesis. c-Met conditional knockout mice (c-met fl/fl , AlbCre +/À ; MetLivKO) treated with N-nitrosodiethylamine developed significantly more and bigger tumors and with a shorter latency compared with control (w/w, AlbCre +/À ; Cre-Ctrl) mice. Accelerated tumor development was associated with increased rate of cell proliferation and prolonged activation of epidermal growth factor receptor (EGFR) signaling. MetLivKO livers treated with N-nitrosodiethylamine also displayed elevated lipid peroxidation, decreased ratio of reduced glutathione to oxidized glutathione, and up-regulation of superoxide dismutase 1 and heat shock protein 70, all consistent with increased oxidative stress. Likewise, gene expression profiling done at 3 and 5 months after N-nitrosodiethylamine treatment revealed up-regulation of genes associated with cell proliferation and stress responses in c-Met mutant livers. The negative effects of c-Met deficiency were reversed by chronic p.o. administration of antioxidant N-acetyl-L-cysteine. N-acetyl-L-cysteine blocked the EGFR activation and reduced the N-nitrosodiethylamineinitiated hepatocarcinogenesis to the levels of Cre-Ctrl mice. These results argue that intact HGF/c-Met signaling is essential for maintaining normal redox homeostasis in the liver and has tumor suppressor effect(s) during the early stages of Nnitrosodiethylamine-induced hepatocarcinogenesis.

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“…Second, they may act to inactivate critical glutathione (GSH)-sensitive, membrane-bound phosphatases necessary for dephosphorylation (turning off) of the growth factor receptor signaling (Knebel et al, 1996;Lee et al, 1998). Recently, Meves et al (2001) proposed that EGFR phosphorylation by hydrogen peroxide and other oxidative stress-inducing agents is preceded by GSH depletion and intracellular hydrogen peroxide accumulation.…”

Section: Erk Pathwaymentioning

confidence: 99%

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

Martindale

Holbrook

2002

Journal Cellular Physiology

2,100

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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H2O2 mediates oxidative stress-induced epidermal growth factor receptor phosphorylation

Cited by 58 publications

References 37 publications

The enhanced tumor inhibitory effects of gefitinib and L-ascorbic acid combination therapy in non-small cell lung cancer cells

The enhanced tumor inhibitory effects of gefitinib and L-ascorbic acid combination therapy in non-small cell lung cancer cells

Loss of Hepatocyte Growth Factor/c-Met Signaling Pathway Accelerates Early Stages of N-nitrosodiethylamine–Induced Hepatocarcinogenesis

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

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