Inhibition of the epidermal growth factor receptor increases expression of genes that stimulate inflammation, apoptosis, and cell attachment

Woodworth, Craig D.; Michael, Evan; Marker, Daniel F.; Allen, Sarah E.; Smith, Laura A.; Nees, Matthias

doi:10.1158/1535-7163.mct-04-0238

Cited by 106 publications

(71 citation statements)

References 45 publications

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“…EGFR is a receptor tyrosine kinase which can activate a number of downstream signaling pathways (reviewed in reference 10). It has been shown that inhibition of EGFR increases the expression of proinflammatory and apoptotic genes (46). Our finding that EGFR shows decreased activity during P2 infection and increased activity at 6 days following P18 infection is consistent with our hypothesis that P2 facilitates a normal, proinflammatory response early in infection, allowing clearance of the virus.…”

Section: Discussionsupporting

confidence: 91%

Identification of Differentially Activated Cell-Signaling Networks Associated with Pichinde Virus Pathogenesis by Using Systems Kinomics

Bowick¹,

Fennewald²,

Scott³

et al. 2007

J Virol

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Phosphorylation plays a key role in regulating many signaling pathways. Although studies investigating the phosphorylated forms of signaling pathways are now commonplace, global analysis of protein phosphorylation and kinase activity has lagged behind genomics and proteomics. We have used a kinomics approach to study the effect of virus infection on host cell signaling in infected guinea pigs. Delineating the host responses which lead to clearance of a pathogen requires the use of a matched, comparative model system. We have used two passage variants of the arenavirus Pichinde, used as a biosafety level 2 model of Lassa fever virus as it produces similar pathologies in guinea pigs and humans, to compare the host cell responses between infections which lead to either a mild, self-limiting infection or lethal disease. Using this model, we can begin to understand the differences in signaling events which give rise to these markedly different outcomes. By contextualizing these data using pathway analysis, we have identified key differences in cellular signaling matrices. By comparing these differentially involved networks, we have identified a number of key signaling "nodes" which show differential phosphorylations between mild and lethal infections. We believe that these nodes provide potential targets for the development of antiviral therapies by acting at the level of the host response rather than by directly targeting viral proteins.

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Section: Discussionsupporting

confidence: 91%

Identification of Differentially Activated Cell-Signaling Networks Associated with Pichinde Virus Pathogenesis by Using Systems Kinomics

Bowick¹,

Fennewald²,

Scott³

et al. 2007

J Virol

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“…The pathophysiology of this new dermatologic entity has not been fully elucidated, but the leading hypothesis is that the keratinocytes of the basal layer of the epidermis react to EGFR inhibition by secreting cytokines that trigger an inflammatory response that eventually causes loss of skin barrier protection and secondary skin infections involving mainly the hair follicles (11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

The Phosphatase Inhibitor Menadione (Vitamin K3) Protects Cells from EGFR Inhibition by Erlotinib and Cetuximab

Pérez-Soler

Zou

et al. 2011

Clinical Cancer Research

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Purpose: Skin toxicity is the main side effect of epidermal growth factor receptor (EGFR) inhibitors, often leading to dose reduction or discontinuation. We hypothesized that phosphatase inhibition in the skin keratinocytes may prevent receptor dephosphorylation caused by EGFR inhibitors and be used as a new potential strategy for the prevention or treatment of this side effect.Experimental Design: Menadione (Vitamin K3) was used as the prototype compound to test our hypothesis. HaCat human skin keratinocyte cells and A431 human squamous carcinoma cells were used. EGFR inhibition was measured by Western blotting and immunofluorescence. Phosphatase inhibition and reactive oxygen species (ROS) generation were measured by standard ELISA and fluorescence assays.Results: Menadione caused significant and reversible EGFR activation in a dose-dependent manner starting at nontoxic concentrations. EGFR activation by menadione was associated with reversible protein tyrosine phosphatase inhibition, which seemed to be mediated by ROS generation as exposure to antioxidants prevented both menadione-induced ROS generation and phosphatase inhibition. Short-term coincubation of cells with nontoxic concentrations of menadione and the EGFR inhibitors erlotinib or cetuximab prevented EGFR dephosphorylation. Seventy-two-hour coincubation of cells with the highest nontoxic concentration of menadione and erlotinib provided for a fourfold cell growth inhibitory protection in HaCat human keratinocyte cells.Conclusions: Menadione at nontoxic concentrations causes EGFR activation and prevents EGFR dephosphorylation by erlotinib and cetuximab. This effect seems to be mediated by ROS generation and secondary phosphatase inhibition. Mild oxidative stress in skin keratinocytes by topical menadione may protect the skin from the toxicity secondary to EGFR inhibitors without causing cytotoxicity. Clin Cancer Res; 17(21); 6766-77. Ó2011 AACR.

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“…Epidermal growth factor receptor (EGFR) is highly expressed in many tumours, including those of the cervix, and there is a clear relationship between HPV E6/E7 oncoproteins and EGFR function (Hu et al, 1997). Blockade of EGFR in cervical cancer cell lines induces increased expression of genes that stimulate apoptosis and suppresses experimental metastasis (Kim et al, 2004;Woodworth et al, 2005). Fibroblast growth factor 1 (FGF1) is a growth factor for both tumour and stromal (endothelial) cells and induces the expression of matrix metalloproteinases (MMPs) and angiogenesis in cancer, hence its involvement in tumour progression (Aonuma et al, 1998;Kwabi-Addo et al, 2004;Udayakumar et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Molecular profiling of cervical cancer progression

Hagemann

Božanović²,

Hooper

et al. 2007

Br J Cancer

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Most cancer patients die of metastatic or recurrent disease, hence the importance to identify target genes upregulated in these lesions. Although a variety of gene signatures associated with metastasis or poor prognosis have been identified in various cancer types, it remains a critical problem to identify key genes as candidate therapeutic targets in metastatic or recurrent cancer. The aim of our study was to identify genes consistently upregulated in both lymph node micrometastases and recurrent tumours compared to matched primary tumours in human cervical cancer. Taqman Low-Density Arrays were used to analyse matched tumour samples, obtained after laser-capture microdissection of tumour cell islands for the expression of 96 genes known to be involved in tumour progression. Immunohistochemistry was performed for a panel of up-and downregulated genes. In lymph node micrometastases, most genes were downregulated or showed expressions equal to the levels found in primary tumours. In more than 50% of lymph node micrometastases studied, eight genes (AKT, BCL2, CSFR1, EGFR1, FGF1, MMP3, MMP9 and TGF-b) were upregulated at least two-fold. Some of these genes (AKT and MMP3) are key regulators of epithelial -mesenchymal transition in cancer. In recurrent tumours, almost all genes were upregulated when compared to the expression profiles of the matched primary tumours, possibly reflecting their aggressive biological behaviour. The two genes showing a consistent downregulated expression in almost all lymph node metastases and recurrent tumours were BAX and APC. As treatment strategies are very limited for metastatic and recurrent cervical cancer, the upregulated genes identified in this study are potential targets for new molecular treatment strategies in metastatic or recurrent cervical cancer.

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Inhibition of the epidermal growth factor receptor increases expression of genes that stimulate inflammation, apoptosis, and cell attachment

Cited by 106 publications

References 45 publications

Identification of Differentially Activated Cell-Signaling Networks Associated with Pichinde Virus Pathogenesis by Using Systems Kinomics

Identification of Differentially Activated Cell-Signaling Networks Associated with Pichinde Virus Pathogenesis by Using Systems Kinomics

The Phosphatase Inhibitor Menadione (Vitamin K3) Protects Cells from EGFR Inhibition by Erlotinib and Cetuximab

Molecular profiling of cervical cancer progression

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