Published ahead of print on June 9, 2005, doi:10.1164/rccm.200411-1523OC Am. J. Respir. Crit. Care Med., Volume 172, Number 5, September 2005, 597-605 A more recent version of this article appeared on September 1, 2005
Submitted on November 15, 2004 Abnormalities in Nitric Oxide and its Derivatives in Lung CancerFares A Masri1,1 Department of Pathobiology, Cleveland Clinic Foundation, Cleveland, Ohio, USA; Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, USA; Department of Chemistry, Cleveland State University, Cleveland, Ohio, USA, 2 Department of Pathobiology, Cleveland Clinic Foundation, Cleveland, Ohio, USA; Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, USA, 3 Department of Pathobiology, Cleveland Clinic Foundation, Cleveland, Ohio, USA, 4 Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, USA, 5 Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA * To whom correspondence should be addressed. E-mail: aulakk{at}ccf.org.
A cellular pro-oxidant 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. To determine the alteration in these NO derivatives and the role they may play in contributing to lung carcinogenesis, we analyzed levels of NO, nitrite (NO2-), nitrate (NO3-), location of the protein nitration and identified the proteins that are modified. Although exhaled NO and NO2- were increased, eNOS or iNOS 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, (2D PAGE; mass spectrometry. Both the degree of nitration and the protein nitration profile was altered. We identified over 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. This study provides evidence in favor of a role for reactive nitrogen and oxygen species in lung cancer. Key words: Nitric oxide, Protein Nitration, Lung cancer, Nitrotyrosine, Proteomics
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