Abnormalities in Nitric Oxide and Its Derivatives in Lung Cancer

Abstract

Rationale: A cellular prooxidant state promotes cells to neoplastic growth, in part because of modification of proteins and their functions. Reactive nitrogen species formed from nitric oxide (NO) or its metabolites, can lead to protein tyrosine nitration, which is elevated in lung cancer. Objective: To determine the alteration in these NO derivatives and the role they may play in contributing to lung carcinogenesis. Methods: We analyzed levels of NO, nitrite (NO 2 Ϫ ), nitrate (NO 3 Ϫ ), and the location of the protein nitration and identified the proteins that are modified. Measurements and Main Results: Although exhaled NO and NO 2 Ϫ were increased, endothelial NO synthase or inducible NO synthase expression was similar in the tumor and tumor-free regions. However, immunohistochemistry showed that nitrotyrosine was increased in the tumor relative to non-tumor-bearing sections. We used proteomics to identify the modified proteins (two-dimensional polyacrylamide gel electrophoresis; mass spectrometry). Both the degree of nitration and the protein nitration profile were altered. We identified more than 25 nitrated proteins, including metabolic enzymes, structural proteins, and proteins involved in prevention of oxidative damage. Alterations of the biology of NO metabolites and nitration of proteins may contribute to the mutagenic processes and promote carcinogenesis. Conclusions: This study provides evidence in favor of a role for reactive nitrogen and oxygen species in lung cancer.Keywords: lung cancer; nitric oxide; nitrotyrosine; protein nitration; proteomics Nitric oxide (NO) plays a variety of regulatory roles in vivo, including control of vascular tone and host defense. However, recent data have suggested that NO metabolites, such as nitrite or NO-modified peptides or proteins, may also play important physiologic roles. Enzymatic generation of NO in mammals is by three isoforms of NO synthase (NOS), inducible NOS (iNOS), endothelial NOS (eNOS), and neuronal NOS (nNOS) (1). The function and regulation of these proteins reflect the role they play in normal physiology. Excessive or inappropriate production of endogenous or exogenous reactive oxygen species (ROS) and NO are implicated in the pathogenesis of cancer (2, 3). For example, cigarette smoke, a major source of exogenous oxidants, is associated with the development of lung cancer (2, 4). Furthermore, cigarette smoking leads to chronic airway inflammation (Received in original form November 15, 2004; accepted in final form May 18, 2005) Supported in part by grants HL60917, AI70649, HL076491, CA53914, and HL04265 from the National Institutes of Health; Debartolo Endowed Funds; American Heart Association 0325313B; a Betsy DeWindt American Cancer Society fellowship, GCRC M01RR018390; and Cafaro Endowed Funds. with accumulation and activation of leukocytes, which produce high levels of ROS and NO. Both these processes lead to oxidative damage (5). Although it is generally accepted that the prooxidant state promotes cells to neoplastic growth through DNA ...

Part I. Molecular and cellular characterization of high nitric oxide-adapted human breast adenocarcinoma cell lines

“…As indicated in our prior works, a number of tumor cell lines have been adapted to HNO concentration levels including those from lung [11,[46][47][48], head and neck [3,[49][50][51][52], and breast [7], suggesting that NO adaptation is also a universal property. In an attempt to further elucidate the impact of extended exposure from NO on underlying biological systems, we herein characterize the four newly The ten most up-regulated appear first and the ten most down-regulated appear below within each cell line type NA not available a Gene symbols used vary according to the supplier of the gene chip created breast adenocarcinoma HNO cell lines [7], along with each respective parent cell line.…”

Eryngium foetidum Suppresses Inflammatory Mediators Produced by Macrophages

“…Lipopolysaccharide-induced macrophage activates iNOS isoform expression and NO production through the activation of NF-κB and MAPKs signaling pathway (Kim et al, 2006). This inducible isoform expresses in several human malignant tumors (Hajri et al, 1998;Klotz et al, 1998;Weninger et al, 1998;Lagares-Garcia et al, 2001;Masri et al, 2005). Nitric oxide plays physiological role in modulation of vascular tone, inhibits platelet aggregation, and induces cell apoptosis (Boscá et al, 2005).…”

Relationships between chronic obstructive pulmonary disease and lung cancer: biological insights

“…In line with this, it has also been well established that patients with underlying respiratory conditions such as chronic obstructive pulmonary disease (COPD), which also represents a major cause of morbidity and mortality in developed countries, exhibit a significantly greater risk of LC (3,(10)(11)(12)(13)(14)(15)(16)(17). Importantly, in patients with moderate-to-severe COPD, the prevalence of LC can go up as high as five-fold that of smokers without the disease (18)(19)(20)(21)(22)(23)(24). Furthermore, the epidemiologic relevance of emphysema in the development of LC in patients with COPD has also been highlighted (2)(3)(4)(5)16).…”

“…For instance, oxidative and nitrosative stress as a result of reactive oxygen and nitrogen species (ROS and RNS, respectively) were shown to favor carcinogenesis through the activation of cellular processes that result in neoplastic transformation or the induction of DNA mutations (32). Other investigations have also demonstrated the contribution of oxidative damage, inflammatory events, and tumor microenvironment to lung carcinogenesis in patients and animal models (19,20,(25)(26)(27)(28)(29)(30)(31)(33)(34)(35)(36)(37).…”