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Modulation of DNA adducts, metabolism, and epigenetic marks in cultured normal human cells supplemented with benz[a]pyrene, NAD+, succinate and/or fumarate: implications to tumorigenesis

Abstract

There is a need to understand how metabolic alterations can contribute to modulating the activity of signaling pathways, transcription factors and epigenetic marks that promote cell proliferation, which may have implications for cancer prevention and treatment.Benzo[a]pyrene (B[a]P) is a carcinogen widespread in the environment and is used in our studies to induce malignant transformation in immortalized human bronchial epithelial cells (BEAS-2B). In the characterized model we observed that: i) cells exposed to B[a]P presented changes in intermediary metabolism within the first hour of exposure, with initial drop of NAD+, NADH, NADPH, ATP, ADP, pyruvate, lactate, succinate, malate, glutamate and glutamine levels, followed by a significant increase of the levels of these molecules and fumarate over 7 days of incubation, compared to the control; ii) the observed metabolic changes were accompanied by changes in levels of DNA 5-mdC and 5-hmdC and increased colony growth in soft-agar, without increasing the mutation rate of the HPRT gene.Since NAD+ and NADH regulate the activity of intermediary metabolism enzymes and transcription factors, as well as the expression of genes that encode proteins involved in the control of metabolism and cell growth, and fumarate and succinate are mentioned as oncometabolites, it is intended here to assess the modulation of metabolism, epigenetic marks, expression of some genes controlled by the redox balance NAD+/NADH, the expression of proteins involved in the alteration of metabolism in tumor cells, and cell transformation in BEAS-2B cells supplemented with NAD+, succinate and fumarate in the presence and absence of B[a]P.Data obtained will increase the understanding of the role of metabolic changes induced by xenobiotics (in this case, B[a]P) to tumorigenesis. This is important for effective procedures for cancer chemoprevention, which are required to decrease the social and economic impacts of this serious group of diseases that tends to grow exponentially with the ageing of the population. (AU)

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