Transformation of human bronchial epithelial cells by benzo[a]pyrene: metabolic redox processes and DNA methylation / demethylation

Abstract

Lung cancer is considered a serious health problem worldwide. Its high mortality rate is a direct reflex of the difficulty of early diagnosis and the refractivity of the advanced stages of this malignancy to conventional therapy. Thus, major advances in treatment may arise from a better understanding of the molecular origins of the disease and cellular changes underlying the transformation and proliferation of precancerous cells. One of the most recent promising targets for therapy is the metabolism of malignancies, since it is altered relative to normal non-proliferating cells. The objective of this project is to determine whether metabolic changes induced by the known carcinogen benzo[a]pyrene in human bronchial epithelial cells (BEAS-2B) contributes to epigenetic alterations leading to gene silencing and malignant transformation. Concomitantly, lesions will be evaluated in the DNA of cells in order to check the contribution of the genotoxic pathway for cellular transformation under the conditions used. Although there are published data showing that inactivating mutations of enzymes of the Krebs cycle lead to changes in the levels of 5-mdC and 5-hmdC in DNA, there are no studies that show a relationship between these changes from the action of a carcinogen. Besides contributing to the area with the elucidation of a possible new route of carcinogenic action of benzo[a]pyrene, which may be common to many carcinogens, the experimental design of this project will enable the creation of a base of laboratorial methods that can be used by different groups interested in the relationship between metabolic changes and the development of diseases.