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1.  Lung Injury and Lung Cancer Caused by Cigarette Smoke-Induced Oxidative Stress: Molecular Mechanisms and Therapeutic Opportunities Involving the Ceramide-Generating Machinery and Epidermal Growth Factor Receptor 
Antioxidants & Redox Signaling  2014;21(15):2149-2174.
Abstract
Chronic obstructive pulmonary disease (COPD) and lung cancer are frequently caused by tobacco smoking. However, these diseases present opposite phenotypes involving redox signaling at the cellular level. While COPD is characterized by excessive airway epithelial cell death and lung injury, lung cancer is caused by uncontrolled epithelial cell proliferation. Notably, epidemiological studies have demonstrated that lung cancer incidence is significantly higher in patients who have preexisting emphysema/lung injury. However, the molecular link and common cell signaling events underlying lung injury diseases and lung cancer are poorly understood. This review focuses on studies of molecular mechanism(s) underlying smoking-related lung injury (COPD) and lung cancer. Specifically, the role of the ceramide-generating machinery during cigarette smoke-induced oxidative stress leading to both apoptosis and proliferation of lung epithelial cells is emphasized. Over recent years, it has been established that ceramide is a sphingolipid playing a major role in lung epithelia structure/function leading to lung injury in chronic pulmonary diseases. However, new and unexpected findings draw attention to its potential role in lung development, cell proliferation, and tumorigenesis. To address this dichotomy in detail, evidence is presented regarding several protein targets, including Src, p38 mitogen-activated protein kinase, and neutral sphingomyelinase 2, the major sphingomyelinase that controls ceramide generation during oxidative stress. Furthermore, their roles are presented not only in apoptosis and lung injury but also in enhancing cell proliferation, lung cancer development, and resistance to epidermal growth factor receptor-targeted therapy for treating lung cancer. Antioxid. Redox Signal. 21, 2149–2174.
I. Introduction
II. Oxidative Stress and Pulmonary Disease
A. Smoking, oxidative stress, and inflammation
B. Smoking and emphysema/lung injury: the role of apoptosis in the disease development
III. The Role of Ceramide in Oxidative Stress-Induced Lung Epithelial Apoptosis
A. Neutral sphingomyelinase 2-induced ceramide generation as a specific target in CS-induced lung injury
B. The surprising role of Src in controlling nSMase2/ceramide generation
IV. Oxidative Stress and Lung Cancer
A. Stress-driven endocytosis of tyrosine-phosphorylated EGFR leads to tumorigenesis: the critical role of oxidative stress
1. Canonical EGFR activation, intracellular trafficking, and degradation
2. CS produces H2O2-induced oxidative stress that aberrantly activates EGFR
3. The lack of c-Cbl binding to EGFR causes prolonged proliferation signaling under oxidative stress
4. EGFR perinuclear sorting under oxidative stress
5. An aberrant activated conformation of EGFR under oxidative stress underlies lung cancer resistance to targeted therapy
V. Smoking and Lung Diseases: The Enigmatic Association Between Lung Injury and Lung Cancer
VI. The Dichotomous Response of Airway Epithelial Cells to CS Oxidants: A Critical Role for Src
VII. The Unexpected Role of Ceramide in Cell Proliferation and Tumorigenesis
A. Cell membrane ceramide-enriched signaling platform and stabilization of aberrantly activated EGFR
B. Membrane ordered lipid domains
C. Ceramide selectively displaces cholesterol from ordered lipid domains (rafts)
D. Ceramide/cholesterol ratio affects EGFR and Src
E. Ceramide, EGFR, and Src
F. The link between ceramide and Src underlies their dual roles in apoptosis and proliferation
VIII. Propagation of Oncogenes and miRNA via nSMase2-Dependent Ceramide Generation and Exosome Secretion
IX. Updates on Novel Unresolved Complexities in the Ceramide-Generating Machinery
X. Therapeutic Perspectives
XI. Concluding Remarks
doi:10.1089/ars.2013.5469
PMCID: PMC4215561  PMID: 24684526
2.  Neutral Sphingomyelinase 2 
Chronic obstructive pulmonary disease (COPD) is caused by exposure to cigarette smoke (CS). One mechanism of CS-induced lung injury is aberrant generation of ceramide, which leads to elevated apoptosis of epithelial and endothelial cells in the alveolar spaces. Recently, we discovered that CS-induced ceramide generation and apoptosis in pulmonary cells is governed by neutral sphingomyelinase (nSMase) 2. In the current experiments, we expanded our studies to investigate whether nSMase2 governs ceramide generation and apoptosis in vivo using rodent and human models of CS-induced lung injury. We found that exposure of mice or rats to CS leads to colocalizing elevations of ceramide levels and terminal deoxynucleotidyl transferase mediated X-dUTP nick end labeling–positive cells in lung tissues. These increases are nSMase2 dependent, and are abrogated by treatment with N-acetyl cysteine or anti-nSMase2 small interfering RNA (siRNA). We further showed that mice that are heterozygous for nSMase2 demonstrate significant decrease in ceramide generation after CS exposure, whereas acidic sphingomyelinase (aSMase) knockout mice maintain wild-type ceramide levels, confirming our previous findings (in human airway epithelial cells) that only nSMase2, and not aSMase, is activated by CS exposure. Lastly, we found that lung tissues from patients with emphysema (smokers) display significantly higher levels of nSMase2 expression compared with lung tissues from healthy control subjects. Taken together, these data establish the central in vivo role of nSMase2 in ceramide generation, aberrant apoptosis, and lung injury under CS exposure, underscoring its promise as a novel target for the prevention of CS-induced airspace destruction.
doi:10.1165/rcmb.2009-0422OC
PMCID: PMC3095936  PMID: 20448054
neutral sphingomyelinase2; ceramide; apoptosis; chronic obstructive pulmonary disease; mouse model
3.  Lung Injury and Cancer 
Cigarette smoke has been connected to an array of chronic lung diseases and is a major source of morbidity and mortality. Active smoking is responsible for approximately 90% of lung cancer cases. In addition, cigarette smoke is associated with other chronic pulmonary diseases such as pulmonary edema, chronic bronchitis, and pulmonary emphysema, the last two also termed chronic obstructive pulmonary disease (COPD). Lung cancer and COPD are developed very frequently in chronic cigarette smokers. It has been known for some time that lung cancer incidence increases in patients with COPD. Even the existence of some low-grade emphysema without noticeable airflow obstruction is associated with significantly elevated risk of lung cancer. These recent clinical insights demand new thinking and exploration of novel mechanistic studies to fully understand these observations. Lung injury and repair involve cell death and hyperplasia of airway epithelial cells and infiltration of inflammatory cells. All of these occur simultaneously. The mechanisms of cell death and hyperplasia in the lung constitute two sides of the coin of lung injury and repair. However, most molecular studies in airway epithelial cells center on the mechanism(s) of either cell growth and proliferation or cell death and the ceramide-generating machinery that drives aberrant induction of apoptotic cell death. Very few address both sides of the coin as an outcome of cigarette smoke exposure, which is the focus of this review.
doi:10.1165/rcmb.2010-0220RT
PMCID: PMC2933544  PMID: 20525802
ceramide machinery; EGFR trafficking; cigarette smoke; lung injury; lung cancer
4.  EGF Receptor Exposed to Oxidative Stress Acquires Abnormal Phosphorylation and Aberrant Activated Conformation That Impairs Canonical Dimerization 
PLoS ONE  2011;6(8):e23240.
Crystallographic studies have offered understanding of how receptor tyrosine kinases from the ErbB family are regulated by their growth factor ligands. A conformational change of the EGFR (ErbB1) was shown to occur upon ligand binding, where a solely ligand-mediated mode of dimerization/activation was documented. However, this dogma of dimerization/activation was revolutionized by the discovery of constitutively active ligand-independent EGFR mutants. In addition, other ligand-independent activation mechanisms may occur. We have shown that oxidative stress (ox-stress), induced by hydrogen peroxide or cigarette smoke, activates EGFR differently than its ligand, EGF, thereby inducing aberrant phosphorylation and impaired trafficking and degradation of EGFR. Here we demonstrate that ox-stress activation of EGFR is ligand-independent, does not induce “classical” receptor dimerization and is not inhibited by the tyrosine kinase inhibitor AG1478. Thus, an unprecedented, apparently activated, state is found for EGFR under ox-stress. Furthermore, this activation mechanism is temperature-dependent, suggesting the simultaneous involvement of membrane structure. We propose that ceramide increase under ox-stress disrupts cholesterol-enriched rafts leading to EGFR re-localization into the rigid, ceramide-enriched rafts. This increase in ceramide also supports EGFR aberrant trafficking to a peri-nuclear region. Therefore, the EGFR unprecedented and activated conformation could be sustained by simultaneous alterations in membrane structure under ox-stress.
doi:10.1371/journal.pone.0023240
PMCID: PMC3154401  PMID: 21853092
5.  Cadmium induces an apoptotic response in sea urchin embryos 
Cell Stress & Chaperones  2007;12(1):44-50.
Cadmium is a heavy metal toxic for living organisms even at low concentrations. It does not have any biological role, and since it is a permanent metal ion, it is accumulated by many organisms. In the present paper we have studied the apoptotic effects of continuous exposure to subacute/sublethal cadmium concentrations on a model system: Paracentrotus lividus embryos. We demonstrated, by atomic absorption spectrometry, that the intracellular amount of metal increased during exposure time. We found, using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, that long treatments with cadmium triggered a severe DNA fragmentation. We demonstrated, by immunocytochemistry on whole-mount embryos, that treatment with cadmium causes activation of caspase-3 and cleavage of death substrates α-fodrin and lamin A. Incubating the embryos since fertilization with Z-DEVD FMK, a caspase-3 inhibitor, we found, by immunocytochemistry, that cleavage by caspase-3 and cleavage of death substrates were inactivated.
doi:10.1379/CSC-229R.1
PMCID: PMC1852892  PMID: 17441506

Results 1-5 (5)