Abstract 2541: Effect of carcinogen acrolein on DNA repair and mutagenic susceptibility.

Abstract

Abstract Lung cancer death is the number one cause of cancer death in the United States. Cigarette smoking is the major cause of lung cancer. Cigarette smoke (CS) contains more than 60 human carcinogens. Our early work has demonstrated that acrolein (Acr), one of the most abundant aldehydes in CS, reacts with DNA to form α- and α-hydroxy-1, N2-cyclic propano-dG adducts (α-Acr-dG and α-Acr-dG). The distribution of Acr-dG in the p53 gene coincides with lung cancer p53 mutational spectrum. Acr-dG adducts induce mainly G to T and G to A mutations that are similar to the mutation signature found in the p53 gene in lung cancer. We have also found that Acr inhibits DNA repair. Therefore, we concluded that Acr is a major etiological agent for CS related lung cancer. In this study, we found that Acr-dG adducts are poorly repaired in Acr treated normal human bronchial epithelial (NHBE) cells. Intriguingly, NHBE cell lysates are competent in carrying out in vitro repair synthesis assay using Acr-modified as well as UV-irradiated DNA as substrates. These results indicate that Acr treatment impairs DNA repair function. We found that Acr not only inhibits nucleotide excision repair (NER), it also inhibits base excision repair (BER) and mismatch repair (MMR). Acr does not change the expression of XPA, XPC, hOGG1, PMS2 or MLH1 genes. However, Acr causes a reduction of XPA, XPC, hOGG1, PMS2 and MLH1 proteins and that this effect can be neutralized by the proteosome inhibitor, MG132. We further found that Acr treatment enhances both bulky and oxidative DNA damage-induced mutagenesis. These results indicate that Acr not only damages DNA, but can also modify DNA repair proteins and further cause degradation of these modified repair proteins. We propose that these two detrimental effects contribute to Acr mutagenicity and carcinogenicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2541. doi:1538-7445.AM2012-2541