Src-Mediated EGF Receptor Activation Regulates Ozone-Induced Interleukin 8 Expression in Human Bronchial Epithelial Cells

Wu, Weidong; Wages, Phillip A.; Devlin, Robert B.; Díaz-Sánchez, David; Peden, David B.; Samet, James M.

doi:10.1289/ehp.1307379

Cited by 34 publications

(28 citation statements)

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“…Peculiar Src expression and kinase activity have been found in a number of different tumours, including GCs; these changes in expression could upregulate tyrosine phosphorylation of Cav-1 [29, 30] and inhibit the effects of the cell membrane on EGFR endocytosis [31]. Preclinical experiments have demonstrated that Src kinase activity may activate EGFR activity [32]. Cav-1 and p-Cav-1(Y14) were reduced when BGC-823 cells were treated with DT-13; however, the TPT-treated group had the opposite result (Figure 5C).…”

Section: Resultsmentioning

confidence: 99%

Synergistic combination of DT-13 and topotecan inhibits human gastric cancer via myosin IIA-induced endocytosis of EGF receptor in vitro and in vivo

Lin

Zhao

et al. 2016

Oncotarget

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Combination therapy has a higher success rate for many cancers compared to mono-therapy. The treatment of Topotecan (TPT) on gastric cancer (GC) is limited by its toxicity and the potential drug resistance. We found that the combination of the saponin monomer 13 from the dwarf lilyturf tuber (DT-13), performing anti-metastasis and anti-angiogenesis effects, with TPT synergistically induced apoptotic cytotoxicity in GCs with high EGF receptor (EGFR) expression, which was dependent on DT-13-induced endocytosis of EGFR. With TPT, DT-13 promoted EGFR ubiquitin--mediated degradation through myosin IIA-induced and Src/ caveolin-1 (Cav-1)-induced endocytosis of EGFR; inhibited EGFR downstream signalling and then increased the pro-apoptotic effects. Moreover, the synergistic pro-apoptotic efficacy of DT-13 and TPT in GCs with high EGFR expression was eliminated by both the NM II inhibitor (−)-blebbistatin and MYH-9 shRNA. The combination therapy of DT-13 with TPT showed stronger anti-tumour effects in vivo compared with their individual effects. Moreover, the results of combination therapy revealed selective upregulation of pro-apoptotic activity in TUNEL assays and cleaved caspase-3 and NM IIA in immunohischemical analysis; while specific downregulation of p-extracellular regulated kinase 1/2 (p-ERK1/2), EGFR and Cav-1 in immunohischemical analysis. Collectively, these findings have significant clinical implications for patients with tumours harbouring high EGFR expression due to the possible high sensitivity of this regimen.

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Section: Resultsmentioning

confidence: 99%

Synergistic combination of DT-13 and topotecan inhibits human gastric cancer via myosin IIA-induced endocytosis of EGF receptor in vitro and in vivo

Lin

Zhao

et al. 2016

Oncotarget

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“…EPA 2014; IARC 2010; McHale et al 2012; Smith 2010; Smith et al 2011; Thomas R et al 2012, 2014), ozone (lung inflammation and injury) (U.S. EPA 2013a, 2014; McCullough et al 2014, 2016; Wu et al 2015), and PAHs (lung cancer) (U.S. EPA 2013b, 2014; Mattes et al 2014)].…”

Section: Resultsmentioning

confidence: 99%

“…Evidence for a causal relationship between a specific AOP and adverse effects includes pharmacologic intervention to block identified pathway changes, use of knock-in and knock-out models, or identification of pathway polymorphisms and concomitant amelioration of severity or incidence of the specified adverse outcomes (U.S. EPA 2014; French et al 2015; Hatzimichael and Crook 2013; Kasahara et al 2015; McCullough et al 2014; McHale et al 2012; Smith 2010; Thomas R et al 2014; Wu et al 2015). …”

Section: Resultsmentioning

confidence: 99%

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The Next Generation of Risk Assessment Multi-Year Study—Highlights of Findings, Applications to Risk Assessment, and Future Directions

Cote

Andersen

Ankley

et al. 2016

Environ Health Perspect

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Background:The Next Generation (NexGen) of Risk Assessment effort is a multi-year collaboration among several organizations evaluating new, potentially more efficient molecular, computational, and systems biology approaches to risk assessment. This article summarizes our findings, suggests applications to risk assessment, and identifies strategic research directions.Objective:Our specific objectives were to test whether advanced biological data and methods could better inform our understanding of public health risks posed by environmental exposures.Methods:New data and methods were applied and evaluated for use in hazard identification and dose–response assessment. Biomarkers of exposure and effect, and risk characterization were also examined. Consideration was given to various decision contexts with increasing regulatory and public health impacts. Data types included transcriptomics, genomics, and proteomics. Methods included molecular epidemiology and clinical studies, bioinformatic knowledge mining, pathway and network analyses, short-duration in vivo and in vitro bioassays, and quantitative structure activity relationship modeling.Discussion:NexGen has advanced our ability to apply new science by more rapidly identifying chemicals and exposures of potential concern, helping characterize mechanisms of action that influence conclusions about causality, exposure–response relationships, susceptibility and cumulative risk, and by elucidating new biomarkers of exposure and effects. Additionally, NexGen has fostered extensive discussion among risk scientists and managers and improved confidence in interpreting and applying new data streams.Conclusions:While considerable uncertainties remain, thoughtful application of new knowledge to risk assessment appears reasonable for augmenting major scope assessments, forming the basis for or augmenting limited scope assessments, and for prioritization and screening of very data limited chemicals.Citation:Cote I, Andersen ME, Ankley GT, Barone S, Birnbaum LS, Boekelheide K, Bois FY, Burgoon LD, Chiu WA, Crawford-Brown D, Crofton KM, DeVito M, Devlin RB, Edwards SW, Guyton KZ, Hattis D, Judson RS, Knight D, Krewski D, Lambert J, Maull EA, Mendrick D, Paoli GM, Patel CJ, Perkins EJ, Poje G, Portier CJ, Rusyn I, Schulte PA, Simeonov A, Smith MT, Thayer KA, Thomas RS, Thomas R, Tice RR, Vandenberg JJ, Villeneuve DL, Wesselkamper S, Whelan M, Whittaker C, White R, Xia M, Yauk C, Zeise L, Zhao J, DeWoskin RS. 2016. The Next Generation of Risk Assessment multiyear study—highlights of findings, applications to risk assessment, and future directions. Environ Health Perspect 124:1671–1682; http://dx.doi.org/10.1289/EHP233

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“…Because of differences in EGFR activation by ligand versus c-Src, the EGFR-STAT3 pathway may be favored when the receptor is activated by the loop phosphorylation mechanism. There are conflicting reports as to whether the Tyr1068 STAT3 docking site is a direct target for c-Src kinase activity, or if c-Src-dependent Tyr845 phosphorylation leads to EGFR activation and the subsequent autophosphorylation at EGFR Tyr1068 (49–51). It is also possible that stress-exposed EGFRs are protected from protein tyrosine phosphatases that maintain basal EGFR tyrosine kinase activity (52).…”

Section: The C-src/egfr/stat3 Signaling Axismentioning

confidence: 99%

Stress-induced EGF receptor signaling through STAT3 and tumor progression in triple-negative breast cancer

Balanis

Carlin

2017

Molecular and Cellular Endocrinology

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Elevated STAT3 activity is a hallmark of many epithelial carcinomas particularly in breast cancers where it is known to contribute to tumor progression through a variety of context-dependent biological responses. However, its role downstream of stress-exposed EGF receptors (EGFR) that are transactivated in endosomes independent of exogenous ligand has not been studied. This review discusses how STAT3 signaling induced by therapeutic stress in EGFR-driven triple-negative breast cancers (TNBC) might override normal epithelial homeostatic mechanisms and provide a survival advantage for tumor cells before they leave the primary tumor and spread to distant sites. Despite continued improvements in breast cancer treatment strategies, TNBC is still associated with poor prognosis and high risk of distant recurrence and death. Understanding EGFR-STAT3 signaling mechanisms regulating the earliest steps of tumor progression is a key to discovery of new targeted therapies against TNBC.

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Src-Mediated EGF Receptor Activation Regulates Ozone-Induced Interleukin 8 Expression in Human Bronchial Epithelial Cells

Cited by 34 publications

References 55 publications

Synergistic combination of DT-13 and topotecan inhibits human gastric cancer via myosin IIA-induced endocytosis of EGF receptor in vitro and in vivo

Synergistic combination of DT-13 and topotecan inhibits human gastric cancer via myosin IIA-induced endocytosis of EGF receptor in vitro and in vivo

The Next Generation of Risk Assessment Multi-Year Study—Highlights of Findings, Applications to Risk Assessment, and Future Directions

Stress-induced EGF receptor signaling through STAT3 and tumor progression in triple-negative breast cancer

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