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Review
. 2018 Mar 16;37(1):61.
doi: 10.1186/s13046-018-0728-0.

The interplay of reactive oxygen species and the epidermal growth factor receptor in tumor progression and drug resistance

Meng-Shih Weng  1 , Jer-Hwa Chang  2   3 , Wen-Yueh Hung  4 , Yi-Chieh Yang  4   5 , Ming-Hsien Chien  6   7
Affiliations
Review

The interplay of reactive oxygen species and the epidermal growth factor receptor in tumor progression and drug resistance

Meng-Shih Weng et al. J Exp Clin Cancer Res. .

Abstract

Background: The epidermal growth factor receptor (EGFR) plays important roles in cell survival, growth, differentiation, and tumorigenesis. Dysregulation of the EGFR is a common mechanism in cancer progression especially in non-small cell lung cancer (NSCLC).

Main body: Suppression of the EGFR-mediated signaling pathway is used in cancer treatment. Furthermore, reactive oxygen species (ROS)-induced oxidative stress from mitochondrial dysfunction or NADPH oxidase (NOX) overactivation and ectopic expression of antioxidative enzymes were also indicated to be involved in EGFR-mediated tumor progression (proliferation, differentiation, migration, and invasion) and drug resistance (EGFR tyrosine kinase inhibitor (TKI)). The products of NOX, superoxide and hydrogen peroxide, are considered to be major types of ROS. ROS are not only toxic materials to cells but also signaling regulators of tumor progression. Oxidation of both the EGFR and downstream phosphatases by ROS enhances EGFR-mediated signaling and promotes tumor progression. This review primarily focuses on the recent literature with respect to the roles of the EGFR and ROS and correlations between ROS and the EGFR in tumor progression and EGFR TKI resistance.

Short conclusion: The evidence discussed in this article can serve as a basis for basic and clinical research to understand how to modulate ROS levels to control the development and drug resistance of cancers.

Keywords: Drug resistance; Epidermal growth factor receptor; NADPH oxidase; Oxidation; Reactive oxygen species; Tumor progression.

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Figures

Fig. 1
Fig. 1
Generation of reactive oxygen species (ROS) from mitochondria. O2·− is formed from molecular O2 by the gain of a single electron from electron leakage in the electron transport chain (ETC) of mitochondria. Superoxide dismutase (SOD) enzymes convert two superoxide molecules into hydrogen peroxide (H2O2) and a water (H2O) molecule. Moreover, hydrogen peroxide is converted to the highly reactive ROS, the hydroxyl radical (OH.-), in the presence of iron (Fe2+), which further causes damage to the cell structure including proteins, lipids, membranes, and DNA. Alternatively, hydrogen peroxide can be reduced to water by glutathione (GSH) peroxidase (GPx) or catalase
Fig. 2
Fig. 2
Schematic of possible mechanisms of reactive oxygen species (ROS)-induced tumor progression. Excessive intracellular ROS in cancer cells can regulate growth factor receptors, cell cycle regulators, and mitogen-activated protein kinase (MAPK) signaling that contribute to cancer progression by promoting cell proliferation, survival, migration, invasion, and angiogenesis
Fig. 3
Fig. 3
Roles of NADPH oxidase (NOX)-derived reactive oxygen species (ROS) in regulating angiogenesis. Hypoxia induces vascular endothelial growth factor (VEGF) production from tumor cells which stimulates NOXs to produce ROS, thereby inducing downstream redox signaling events including expressions of various redox-sensitive transcriptional factors (hypoxia-inducible factor (HIF)-1, redox factor (Ref)-1, nuclear factor (NF)-κB, and activator protein (AP)-1) and genes (VEGF, matrix metalloproteinases (MMPs), cyclooxygenase (COX)-2, and urokinase plasminogen activator (uPA)), which are involved in angiogenesis. ECs, endothelial cells
Fig. 4
Fig. 4
Schematic of the cross-talk between the epidermal growth factor (EGF)-EGF receptor (EGFR) axis and NADPH oxidase (NOX)-mediated reactive oxygen species (ROS) signaling pathways. The binding of EGF to the EGFR induces receptor dimerization and then autophosphorylation of tyrosine (Tyr) residues (red circles) in its cytoplasmic domain. These phosphorylated Tyr residues serve as docking sites for associated proteins which activate multiple pathways. In particular, the Ras/Raf/mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)/Akt pathways downstream of the EGFR play critical roles in cell migration, invasion, proliferation, and survival. Moreover, the EGF-EGFR axis also induces NOX-mediated hydrogen peroxide production, and hydrogen peroxide can diffuse across the membrane to reach the intracellular cytosol. Transient increases in hydrogen peroxide induce oxidation of reduction-oxidation reaction (redox) targets such as phosphatase and tensin homolog (PTEN) to promote Akt activation, protein tyrosine (Tyr) phosphatases (PTPs) to enhance EGFR Tyr phosphorylation, or complex formation of SHC-Grb2-SOS with the EGFR to activate Ras/MAPK signaling. Grb-2, growth factor receptor-bound protein 2; SOS, guanine nucleotide exchange protein
Fig. 5
Fig. 5
Different fates of epidermal growth factor (EGF)-EGF receptor (EGFR) harboring the T790 M mutation in basal and excessive reactive oxygen species (ROS) conditions. a In the basal condition, the EGFR T790 M mutant activates NADPH oxidase 2 (NOX2) to produce ROS, and further oxidizes cysteine (Cys)797 of the EGFR, resulting in mild oxidation of methionine (Met)790. In this condition, basal activity of Met reductase A (MsrA) is fully responsible for reducing the oxidized form of Met790 on the EGFR to the reduced form and protects it from degradation, resulting in cell survival. b Under a condition of sanguinarine-mediated ROS overproduction, a reduction-oxidation reaction (redox) imbalance is induced by activating NOX3 to cause oxidation and depletion of NADPH, resulting in MsrA inactivation and loss of the ability to reduce the oxidized form of Met790 on the EGFR. Excessive amounts of ROS can further induce overoxidation of Met790 on the EGFR and ultimately induce EGFR degradation and cell apoptosis
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References

    1. Wee P, Wang Z. Epidermal growth factor receptor cell proliferation signaling pathways. Cancers (Basel). 2017;9(5):E52. - PMC - PubMed
    1. Tomas A, Futter CE, Eden ER. EGF receptor trafficking: consequences for signaling and cancer. Trends Cell Biol. 2014;24(1):26–34. doi: 10.1016/j.tcb.2013.11.002. - DOI - PMC - PubMed
    1. Cooper WA, Lam DC, O'Toole SA, Minna JD. Molecular biology of lung cancer. J Thorac Dis. 2013;5(Suppl 5):S479–S490. - PMC - PubMed
    1. Liu TC, Jin X, Wang Y, Wang K. Role of epidermal growth factor receptor in lung cancer and targeted therapies. Am J Cancer Res. 2017;7(2):187–202. - PMC - PubMed
    1. Davidson MR, Gazdar AF, Clarke BE. The pivotal role of pathology in the management of lung cancer. J Thorac Dis. 2013;5(Suppl 5):S463–S478. - PMC - PubMed

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