Heparin-Binding Epidermal Growth Factor-Like Growth Factor Inhibits Cytokine-Induced NF-κB Activation and Nitric Oxide Production via Activation of the Phosphatidylinositol 3-Kinase Pathway

Mehta, Veela B.; Besner, Gail E.

doi:10.4049/jimmunol.175.3.1911

Cited by 25 publications

(14 citation statements)

References 41 publications

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“…However, we are the first to report the involvement of the NF-nB pathway, specifically downstream of AR-stimulated EGFR in breast cancer. Our findings of a specific regulation of NF-nB by AR in breast cancer cells are in contrast with other studies on HB-EGF and TGF-a in intestinal epithelial cells and vascular endothelium, respectively (56,57). Additionally, our data also are in contrast with work from Biswas et al, showing that EGF activates NF-nB in ERÀ breast cancer cell lines (59).…”

Section: Discussioncontrasting

confidence: 99%

“…However, previous research has not fully characterized the role of ligand specificity in regulating that activation of NF-nB by EGFR. The EGFR ligand HB-EGF has been shown to inhibit NF-nB activation in intestinal epithelial cells in a phosphoinositide-3 kinase -dependent manner (56), and TGF-a can induce NF-nB in the vascular wall in response to stress (57). Furthermore, EGF has been implicated in NF-nB activation in fibroblasts due to interactions between Grb7 and NF-nB -inducing kinase (58) and in the ERÀ breast cancer cell lines MDA-MB-231 and MDA-MB-435 cells, although a mechanism describing these effects was not explored (59).…”

Section: Discussionmentioning

confidence: 99%

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Activation of a Nuclear Factor κB/Interleukin-1 Positive Feedback Loop by Amphiregulin in Human Breast Cancer Cells

Streicher

Willmarth

García

et al. 2007

Molecular Cancer Research

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We have recently shown that an amphiregulin-mediated autocrine loop is responsible for growth factorindependent proliferation, motility, and invasive capacity of some aggressive breast cancer cells, such as the SUM149 breast cancer cell line. In the present study, we investigated the mechanisms by which amphiregulin activation of the epidermal growth factor receptor (EGFR) regulates these altered phenotypes. Bioinformatic analysis of gene expression networks regulated by amphiregulin implicated interleukin-1A (IL-1A) and IL-1B as key mediators of amphiregulin's biological effects. The bioinformatic data were validated in experiments which showed that amphiregulin, but not epidermal growth factor, results in transcriptional up-regulation of IL-1A and IL-1B. Both IL-1A and IL-1B are synthesized and secreted by SUM149 breast cancer cells, as well as MCF10A cells engineered to express amphiregulin or MCF10A cells cultured in the presence of amphiregulin. Furthermore, EGFR, activated by amphiregulin but not epidermal growth factor, results in the prompt activation of the transcription factor nuclear factor -KB (NF-KB), which is required for transcriptional activation of IL-1. Once synthesized and secreted from the cells, IL-1 further activates NF-KB, and inhibition of IL-1 with the IL-1 receptor antagonist results in loss of NF-KB DNA binding activity and inhibition of cell proliferation. However, SUM149 cells can proliferate in the presence of IL-1 when EGFR activity is inhibited. Thus, in aggressive breast cancer cells, such as the SUM149 cells, or in normal human mammary epithelial cells growing in the presence of amphiregulin, EGFR signaling is integrated with NF-KB activation and IL-1 synthesis, which cooperate to regulate the growth and invasive capacity of the cells. (Mol Cancer Res 2007;5(8):847 -62)

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Activation of a Nuclear Factor κB/Interleukin-1 Positive Feedback Loop by Amphiregulin in Human Breast Cancer Cells

Streicher

Willmarth

García

et al. 2007

Molecular Cancer Research

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“…In osteoblasts, the PI3K/Akt pathway functions downstream of the extracellular stimuli that activate integrin/focal adhesion kinase (56). Alternatively, heparin may interact with heparin binding epidermal growth factor to activate the PI3K pathway, as has been found in other cell/tissue types (57,58). Further investigations are required to distinguish among these possibilities.…”

Section: Discussionmentioning

confidence: 99%

Synergism between Wnt3a and Heparin Enhances Osteogenesis via a Phosphoinositide 3-Kinase/Akt/RUNX2 Pathway

Ling

Dombrowski

Foong

et al. 2010

Journal of Biological Chemistry

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A new strategy has emerged to improve healing of bone defects using exogenous glycosaminoglycans by increasing the effectiveness of bone-anabolic growth factors. Wnt ligands play an important role in bone formation. However, their functional interactions with heparan sulfate/heparin have only been investigated in non-osseous tissues. Our study now shows that the osteogenic activity of Wnt3a is cooperatively stimulated through physical interactions with exogenous heparin. N-Sulfation and to a lesser extent O-sulfation of heparin contribute to the physical binding and optimal co-stimulation of Wnt3a. Wnt3a-heparin signaling synergistically increases osteoblast differentiation with minimal effects on cell proliferation. Thus, heparin selectively reduces the effective dose of Wnt3a needed to elicit osteogenic, but not mitogenic responses. Mechanistically, Wnt3a-heparin signaling strongly activates the phosphoinositide 3-kinase/Akt pathway and requires the bone-related transcription factor RUNX2 to stimulate alkaline phosphatase activity, which parallels canonical ␤-catenin signaling. Collectively, our findings establish the osteo-inductive potential of a heparinmediated Wnt3a-phosphoinositide 3-kinase/Akt-RUNX2 signaling network and suggest that heparan sulfate supplementation may selectively reduce the therapeutic doses of peptide factors required to promote bone formation.

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“…38 Finally, EGFR also controls PI3K activity both in the endothelium and smooth muscle cells as demonstrated previously using pharmacological agents and the wa-2 mice. 39,40 Further studies should address this point.…”

Section: Discussionmentioning

confidence: 99%

Epidermal Growth Factor Receptor Mediates the Vascular Dysfunction But Not the Remodeling Induced by Aldosterone/Salt

et al. 2011

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Abstract-Pathophysiological aldosterone (aldo)/mineralocorticoid receptor signaling has a major impact on the cardiovascular system, resulting in hypertension and vascular remodeling. Mineralocorticoids induce endothelial dysfunction, decreasing vasorelaxation in response to acetylcholine and increasing the response to vasoconstrictors. Activation of the epidermal growth factor receptor (EGFR) is thought to mediate the vascular effects of aldo, but this has yet to be demonstrated in vivo. In this study, we analyzed the molecular and functional vascular consequences of aldo-salt challenge in the waved 2 mouse, a genetic model with a partial loss of EGFR tyrosine kinase activity. Deficient EGFR activity is associated with global oxidative stress and endothelial dysfunction. A decrease in EGFR activity did not affect the arterial wall remodeling process induced by aldo-salt. By contrast, normal EGFR activity was required for the aldo-induced enhancement of phenylephrine-and angiotensin II-mediated vasoconstriction. In conclusion, this in vivo study demonstrates that EGFR plays a key role in aldosterone-mediated vascular reactivity. Clinical trials (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study and Randomized Aldactone Evaluation Study) have demonstrated the beneficial effects of administering low doses of pharmacological antagonists of the mineralocorticoid receptor (MR; the receptor of the mineralocorticoid hormone aldosterone [aldo]) to patients with heart failure, with improvements in survival rate and morbidity. 1,2 These clinical benefits may partly result from improved vascular function. 3 The MR is expressed in both endothelium and smooth muscle, 4 and the vessels are now considered to be direct targets of aldo. 5 In the mouse, the 11␤-hydroxysteroid dehydrogenase type II enzyme is expressed in the endothelium but not in the smooth muscle, 4,6 at variance with humans. 7 Therefore, in the mouse, aldo is the specific ligand of the MR in the endothelium but not in the smooth muscle, where glucocorticoids could also activate MR. MR activation affects endothelial function and vascular tone: aldo infusion induces endothelial dysfunction, decreasing vasorelaxation in response to acetylcholine (Ach), and increasing the response to various vasoconstrictors. 5,8,9 We showed recently that an increase in MR signaling in the endothelium is associated with an increase in blood pressure and altered vascular tone. 4 Moreover, patients with primary aldosteronism have a higher aortic wall thickness than those with primary hypertension. 10 Aldo is, thus, recognized as a cardiovascular risk factor that exacerbates vascular injury, 3 although the underlying mechanisms remain unclear.It has been suggested that the epidermal growth factor receptor (EGFR) could play a key role in the cardiovascular effects of aldo. 11 In cultured cells, downstream EGFR signaling cascades are induced by aldo or prevented by MR blockade on aldo stimulation. 12 Increases in EGFR expression and/or activation have...

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Heparin-Binding Epidermal Growth Factor-Like Growth Factor Inhibits Cytokine-Induced NF-κB Activation and Nitric Oxide Production via Activation of the Phosphatidylinositol 3-Kinase Pathway

Cited by 25 publications

References 41 publications

Activation of a Nuclear Factor κB/Interleukin-1 Positive Feedback Loop by Amphiregulin in Human Breast Cancer Cells

Activation of a Nuclear Factor κB/Interleukin-1 Positive Feedback Loop by Amphiregulin in Human Breast Cancer Cells

Synergism between Wnt3a and Heparin Enhances Osteogenesis via a Phosphoinositide 3-Kinase/Akt/RUNX2 Pathway

Epidermal Growth Factor Receptor Mediates the Vascular Dysfunction But Not the Remodeling Induced by Aldosterone/Salt

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