Erlotinib-Mediated Inhibition of EGFR Signaling Induces Metabolic Oxidative Stress through NOX4

Orcutt, Kevin P.; Parsons, Arlene D.; Sibenaller, Zita A.; Scarbrough, Peter M.; Zhu, Yueming; Sobhakumari, Arya; Wilke, Werner W.; Kalen, Amanda L.; Goswami, Prabhat C.; Miller, Francis J.; Spitz, Douglas R.; Simons, Andrean L.

doi:10.1158/0008-5472.can-10-3425

Cited by 76 publications

(67 citation statements)

References 30 publications

(31 reference statements)

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“…Furthermore, increased NOX4 expression under conditions of reduced EGFR activity has been reported before. 36,37 Possibly, the ROS dysbalance is not strong enough to elicit major fibrotic alterations.…”

Section: Discussionmentioning

confidence: 99%

Loss of Epidermal Growth Factor Receptor in Vascular Smooth Muscle Cells and Cardiomyocytes Causes Arterial Hypotension and Cardiac Hypertrophy

et al. 2013

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Abstract-The epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, contributes to parainflammatory dysregulation, possibly causing cardiovascular dysfunction and remodeling. The physiological role of cardiovascular EGFR is not completely understood. To investigate the physiological importance of EGFR in vascular smooth muscle cells and cardiomyocytes, we generated a mouse model with targeted deletion of the EGFR using the SM22 (smooth muscle-specific protein 22) promoter. While the reproduction of knockout animals was not impaired, life span was significantly reduced. Systolic blood pressure was not different between the 2 genotypes-neither in tail cuff nor in intravascular measurementswhereas total peripheral vascular resistance, diastolic blood pressure, and mean blood pressure were reduced. Loss of vascular smooth muscle cell-EGFR results in a dilated vascular phenotype with minor signs of fibrosis and inflammation. Echocardiography, necropsy, and histology revealed a dramatic eccentric cardiac hypertrophy in knockout mice (2.5-fold increase in heart weight), with increased stroke volume and cardiac output as well as left ventricular wall thickness and lumen. Cardiac hypertrophy is accompanied by an increase in cardiomyocyte volume, a strong tendency to cardiac fibrosis and inflammation, as well as enhanced NADPH-oxidase 4 and hypertrophy marker expression. Thus, in cardiomyocytes, EGFR prevents excessive hypertrophic growth through its impact on reactive oxygen species balance, whereas in vascular smooth muscle cells EGFR contributes to the appropriate vascular wall architecture and vessel reactivity, thereby supporting a physiological vascular tone.

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Section: Discussionmentioning

confidence: 99%

Loss of Epidermal Growth Factor Receptor in Vascular Smooth Muscle Cells and Cardiomyocytes Causes Arterial Hypotension and Cardiac Hypertrophy

et al. 2013

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“…17 These processes are known to be associated with the induction of autophagy 4 and thus, we hypothesized that autophagy would be activated in cancer cells that were treated with erlotinib. Furthermore, autophagy has been shown to be activated, to varying degrees, as a response to EGFR targeted therapies.…”

Section: Egfr Tyrosine Kinase Inhibition Induces Lc3 Lipidationmentioning

confidence: 99%

EGFR tyrosine kinase inhibition induces autophagy in cancer cells

Fung

Chen

Grandis

et al. 2012

Cancer Biology & Therapy

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“…Following 24h erlotinib treatment, the levels of glucose uptake and GSH, as well as the activities of HK2 were sharply reduced (Fig 3a). 16,17 , but the same two metabolic phenotypes, corresponding to the same fractions of the total population, are still resolved (Supporting Fig S11b). This opens up biological questions that will be pursued elsewhere, but also points to the value of such integrated proteomic/metabolite single cell assays for uncovering new biology.…”

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confidence: 94%

Chemical Methods for the Simultaneous Quantitation of Metabolites and Proteins from Single Cells

Xue

Wei

et al. 2015

J. Am. Chem. Soc.

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We describe chemical approaches for integrated metabolic and proteomic assays from single cells. Quantitative assays for intracellular metabolites, including glucose uptake and 3 other species, are designed as surface-competitive binding assays with fluorescence readouts. This enables integration into a micro-array format with functional protein immunoassays, all of which are incorporated into the microchambers of a single-cell barcode chip (SCBC). Using the SCBC, we interrogate the response of human-derived glioblastoma cancer cells to EGFR inhibition. We report, for the first time, on both the intercellular metabolic heterogeneity as well as the baseline and drug-induced changes in the metabolite-phosphoprotein correlation network. Graphical AbstractThe emergence of powerful single-cell genomic, transcriptomic, and proteomic tools over the past decade has yielded exciting approaches towards resolving the heterogeneity of complex biological systems. [1][2][3] To date, most single cell tools have focused on transcriptome or proteome analysis, or on the sequencing of specific sets of genes. Quantitative single cell metabolic assays have proven more challenging, although there mass spectrometric methods are promising. [4][5][6] No reports on the integration of metabolite assays with other classes of Corresponding Author. ; Email: heath@caltech.edu (J.R.H.) # These authors contributed equally. ASSOCIATED CONTENT Supporting InformationSynthetic schemes, experimental details and statistical methods. This material is available free of charge via the Internet at http:// pubs.acs.org.The authors declare no competing financial interests. Quantitative measurements (generating copy numbers per cell) of intracellular proteins can be accomplished using calibrated, sandwich-type immunofluorescence assays. Such assays require a surface-bound capture antibody and a fluorophore-labeled detection antibody, and yield an optical readout that correlates with protein copy number. These assays can be miniaturized and multiplexed through spatial addressing using the single cell barcode chip (SCBC) format. Metabolites are small molecules, and so cannot be similarly detected by antibody pairs. We report on three types of spatially-addressable competition assays designed to measure the absolute or relative levels of 4 small molecule metabolites, in a manner that allows those assays to be integrated into SCBC (or other) proteomic assays. HHS Public AccessThe SCBC platform, the metabolite competition assays, and calibration and validation data are provided in Figure 1. The SCBC (Fig 1a) consists of 310 1.5 nanoliter microchambers into which cells are loaded, and each of which contains a full barcode array. Each microchamber has a companion lysis buffer reservoir separated by a programmable valve (Supporting Figure S1). 7,8 For protein assays, specific stripes in the barcode represent a spatial address upon which a sandwich immunofluorescence assay for a specific protein is executed. Each barcode stripe is initially patterned with a ...

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Erlotinib-Mediated Inhibition of EGFR Signaling Induces Metabolic Oxidative Stress through NOX4

Cited by 76 publications

References 30 publications

Loss of Epidermal Growth Factor Receptor in Vascular Smooth Muscle Cells and Cardiomyocytes Causes Arterial Hypotension and Cardiac Hypertrophy

Loss of Epidermal Growth Factor Receptor in Vascular Smooth Muscle Cells and Cardiomyocytes Causes Arterial Hypotension and Cardiac Hypertrophy

EGFR tyrosine kinase inhibition induces autophagy in cancer cells

Chemical Methods for the Simultaneous Quantitation of Metabolites and Proteins from Single Cells

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