Epidermal growth factor receptor reactivation induced by E-prostanoid-3 receptor- and tumor necrosis factor-alpha-converting enzyme-dependent feedback exaggerates interleukin-8 production in airway cancer (NCI-H292) cells.
ABSTRACT Airway epithelial cancer cells produce increased amounts of the chemokine interleukin-8 (IL-8), inducing pro-tumor responses. Multiple stimuli induce airway epithelial IL-8 production epidermal growth factor receptor (EGFR) dependently, but the mechanisms that exaggerate IL-8 production in airway cancers remain unknown. Here we show that direct activation of EGFR (EGFR-P) by its ligand transforming growth factor (TGF)-alpha induces a second EGFR-P in human airway (NCI-H292) cancer cells but not in normal human bronchial epithelial (NHBE) cells, exaggerating IL-8 production in these cancer cells. The second EGFR-P in NCI-H292 cells was caused by metalloprotease TNF-alpha-converting enzyme (TACE)-dependent cleavage of EGFR pro-ligands and was responsible for most of the total IL-8 induced by TGF-alpha. In NCI-H292 cells, TGF-alpha induced cyclooxygenase (COX)-2-dependent prostaglandin (PG)E2 production and release. PGE2 increased the second EGFR-P and IL-8 production via binding to its Gi-protein-coupled E-prostanoid (EP)3 receptor. In NHBE cells, TGF-alpha-induced EGFR-P did not lead to PGE2 production or to a second EGFR-P, and less IL-8 was produced. Thus, we conclude that a positive feedback pathway involving COX-2/PGE2/EP3 receptor-dependent EGFR reactivation exaggerates IL-8 production in NCI-H292 cancer cells but not in NHBE (normal) cells.
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ABSTRACT: Osteosarcoma is the most common malignant bone tumor found in children and adolescents and is associated with many complications including cancer pain and metastasis. While cancer patients often seek complementary and alternative medicine (CAM) approaches to treat cancer pain and fatigue or the side effects of chemotherapy and treatment, there is little known about the effect of acupuncture treatment on tumor growth and metastasis. Here we evaluate the effects of six different electroacupuncture (EA) regimens on osteosarcoma tumor growth and metastasis in both male and female mice. The most significant positive effects were observed when EA was applied to the ST-36 acupoint twice weekly (EA-2X/3) beginning at postimplantation day 3 (PID 3). Twice weekly treatment produced robust reductions in tumor growth. Conversely, when EA was applied twice weekly (EA-2X/7), starting at PID 7, there was a significant increase in tumor growth. We further demonstrate that EA-2X/3 treatment elicits significant reductions in tumor lymphatics, vasculature, and innervation. Lastly, EA-2X/3 treatment produced a marked reduction in pulmonary metastasis, thus providing evidence for EA's potential antimetastatic capabilities. Collectively, EA-2X/3 treatment was found to reduce both bone tumor growth and lung metastasis, which may be mediated in part through reductions in tumor-associated vasculature, lymphatics, and innervation.Evidence-based Complementary and Alternative Medicine 10/2013; 2013:387169. DOI:10.1155/2013/387169 · 2.18 Impact Factor
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ABSTRACT: Mutations in cystic fibrosis transmembrane conductance regulator (CFTR) protein cause cystic fibrosis, a disease characterized by exaggerated airway epithelial production of the neutrophil chemokine interleukin (IL)-8, which results in exuberant neutrophilic inflammation. Because activation of an epidermal growth factor receptor (EGFR) signaling cascade induces airway epithelial IL-8 production, we hypothesized that normal CFTR suppresses EGFR-dependent IL-8 production and that loss of CFTR at the surface exaggerates IL-8 production via activation of a pro-inflammatory EGFR cascade. We examined this hypothesis in human airway epithelial (NCI-H292) cells and in normal human bronchial epithelial (NHBE) cells containing normal CFTR treated with a CFTR-selective inhibitor (CFTR-172), and in human airway epithelial (IB3) cells containing mutant CFTR versus isogenic (C38) cells containing wild-type CFTR. In NCI-H292 cells, CFTR-172 induced IL-8 production EGFR-dependently. Pretreatment with an EGFR neutralizing antibody or the metalloprotease TACE inhibitor TAPI-1, or TACE siRNA knockdown prevented CFTR-172-induced EGFR phosphorylation (EGFR-P) and IL-8 production, implicating TACE-dependent EGFR pro-ligand cleavage in these responses. Pretreatment with neutralizing antibodies to IL-1R or to IL-1alpha, but not to IL-1beta, markedly suppressed CFTR-172-induced EGFR-P and IL-8 production, suggesting that binding of IL-1alpha to IL-1R stimulates a TACE-EGFR-IL-8 cascade. Similarly, in NHBE cells, CFTR-172 increased IL-8 production EGFR-, TACE-, and IL-1alpha/IL-1R-dependently. In IB3 cells, constitutive IL-8 production was markedly increased compared to C38 cells. EGFR-P was increased in IB3 cells compared to C38 cells, and exaggerated IL-8 production in the IB3 cells was EGFR-dependent. Activation of TACE and binding of IL-1alpha to IL-1R contributed to EGFR-P and IL-8 production in IB3 cells but not in C38 cells. Thus, we conclude that normal CFTR suppresses airway epithelial IL-8 production that occurs via a stimulatory EGFR cascade, and that loss of normal CFTR activity exaggerates IL-8 production via activation of a pro-inflammatory EGFR cascade.PLoS ONE 08/2013; 8(8):e72981. DOI:10.1371/journal.pone.0072981 · 3.53 Impact Factor
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ABSTRACT: Increasing evidence of a critical role played by the bronchial epithelium in airway homeostasis is opening new therapeutic avenues. Its unique situation at the interface with the environment suggests that the subtle regulation orchestrated by the epithelium between tolerance and specific immune response might be impaired in asthma. Airway mucus is acting as a physical and a biological fluid between the environment and the epithelium, synergistically moved by the cilia. In asthma, excessive mucus production is a hallmark of airway remodeling. Since many years we tried to therapeutically target mucus hypersecretion, but actually this option is still not achieved. The present review discusses the dynamic processes regulating airway mucus production. Airway inflammation is central in current asthma management. Understanding of how the airway epithelium influences the TH2 paradigm in response to deleterious agents is improving. The multiple receptors expressed by the airway epithelium are the transducers of the biological signals induced by various invasive agents to develop the most adapted response. Airway remodeling is observed in severe chronic airway diseases and may result from ongoing disturbance of signal transduction and epithelial renewal. Chronic airway diseases such as asthma will require assessement of these epithelial abnormalities to identify phenotypic characteristics associated with predicting a clinical benefit for epithelial-directed therapies.Pharmacology [?] Therapeutics 07/2013; DOI:10.1016/j.pharmthera.2013.07.008 · 7.75 Impact Factor