Carcinogenesis Advance Access published online on January 12, 2008
Carcinogenesis, doi:10.1093/carcin/bgn014
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Chemopreventive agents modulate the protein expression profile of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone plus benzo[a]pyrene-induced lung tumors in A/J mice
1 The Cancer Center, Molecular Biology and Biophysics, University of Minnesota, MN 55455, USA
2 Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, MN 55455, USA
* To whom correspondence should be addressed: Fekadu Kassie, University of Minnesota Cancer Center, Mayo Mail Code 806, 420 Delaware St. SE, Minneapolis, MN 55455. Phone: 612 626 5143; Fax:612 626 5135; E-mail: kassi012{at}umn.edu
We used isobaric tag labeling coupled with mass spectrometry to compare the relative abundance of proteins in lung tumors from A/J mice treated with a mixture of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (BaP) versus normal mouse lung tissues. Levels of 59 proteins changed – 30 increased and 29 decreased – in tumor tissues versus normal tissues. Among proteins that showed increased levels in tumor tissues versus normal tissues were glycolytic enzymes, ribosomal proteins, fatty acid synthase (FAS), cathepsins D and H and carbonic anhydrase 2. On the other hand, the levels of cytochrome P450 enzymes 2B10 and 2F2, glutathione S-transferases (GST) mu-1, procollagen VI, Clara cell 10-kDA (CC10) protein, histones, receptor-advanced-glycation-end-product (RAGE), and lung carbonyl reductase were lower in tumor tissues versus normal lung tissues. Upon dietary administration of a combination of N-acetyl-S-(N-2-phenethylthiocarbamoyl)-L-cysteine (PEITC-NAC) plus myo-inositol (MI) or indole-3-carbinol (I3C) to carcinogen-treated mice, the relative abundance of 60S ribosomal protein L4 and carbonic anhydrase in tumor tissues decreased whereas that of histones, GST mu, RAGE, transglutaminase, and procollagen VI increased. Western assays with lung tissue homogenates not only verified the iTRAQ results for selected proteins but also showed differential expression of hypoxia inducible factor-1
(HIF-1), a transcription factor for most of the proteins we found in the iTRAQ study. This is the first report on the application of quantitative proteomics to study the relative abundance of proteins in a mouse model of lung carcinogenesis. These proteins may have utility for development of candidate lung cancer biomarkers and as targets of chemopreventive/chemotherapeutic agents.
Key Words: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone • benzo[a]pyrene • lung • tumor • chemoprevention • iTRAQ proteomics
Received October 16, 2007; revised December 10, 2007; accepted December 17, 2007.
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