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Abnormalities in Nitric Oxide and Its Derivatives in Lung Cancer

Departments of Pathobiology, Pulmonary and Critical Care Medicine, and Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation; and Cleveland State University, Cleveland, Ohio

Correspondence and requests for reprints should be addressed to Kulwant S. Aulak, Ph.D., Cleveland Clinic Foundation, 9500 Euclid Avenue/NB30, Cleveland, OH 44195. E-mail: aulakk{at}ccf.org

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 (NO₂^–), nitrate (NO₃^–), and the location of the protein nitration and identified the proteins that are modified. Measurements and Main Results: Although exhaled NO and NO₂^– 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.

Key Words: lung cancer • nitric oxide • nitrotyrosine • protein nitration • proteomics

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