Study of TSNA Signaling Pathway by Targeted Proteomics
Abstracts
Initial Award Abstract |
While tobacco control achieves a remarkable progress in past 20 years, use of tobacco products continues to be the major cause of lung cancer development in both women and men. In the United States, more than 80% of all lung cancer-related deaths are caused by cigarette smoking and smokeless tobacco use. Sixty chemicals, especially tobacco-specific nitrosamines (TSNAs), such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N\'-nitrosonornicotine (NNN), from tobacco have been known to cause cancer according to the reports from the International Agency for Research on Cancer. Although there is no doubt that TSNAs are closely related to smoking-induced lung cancer, the mechanism of their carcinogenesis remains elusive. One plausible mechanism involves the genotoxic effect of NNK/NNN, which can induce DNA damage and mutations in K-RAS oncogene and p53 tumor suppressor gene. Recently, growing evidence implies that NNK/NNN can also promote the formation of tumor by other mechanisms. Various studies suggest that NNK may induce the release of arachidonic acid (AA) to stimulate extensive growth of human cancer cells by activating beta1- and beta2-adrenergic receptors. Importantly, it has been found that cell membrane proteins, GTP/ATP-binding proteins play a crucial role in most of these proposed TSNA-related mechanisms of lung cancer development.
Given the central role of cell membrane proteins and nucleotide-binding proteins including GTP/ATP-binding proteins in TSNA-related lung cancer development, we reason that quantifying systematically the abundance of membrane proteins and GTP/ATP-binding proteins upon TSNA treatment might provide detailed analysis of the mechanism of TSNA toxicity and offer significant new insights into the mechanisms of smoking-related lung cancer development. Our recent success of chemical enrichment strategy involving specific detection of proteins with functional similarities from cells provide the possibility to purify and quantify membrane and GTP/ATP-binding proteins from human lung cells upon NNK/NNN treatment. The proposed experiments are aimed to detect membrane proteins as well as GTP/ATP-binding proteins in human lung cells that are perturbed upon NNK/NNN exposure. The successful discovery of new membrane proteins and GTP/ATP-binding proteins as TSNA-related targets will offer deep insights into the mechanisms of TSNAs in the smoking-related lung cancer development, driving the development of novel and more effective drugs for lung cancer prevention and treatment.
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