Cancer development in humans and animals may be caused by environmental factors. It has been estimated that approximately 80% of human tumors are generated by exposure to environmental carcinogens. The carcinogens may initiate or induce progression of tumors in several ways. Cellular senescence is a natural barrier used by cells to respond to stress. The molecular analysis of immortal clones shows alterations, either structural or epigenetic, in the genes involved in cellular senescence. It is thought that these alterations are caused directly by mutating or methylating the genes involved in cellular senescence. Therefore, understanding cellular senescence and how it can be modified by environmental carcinogens may be essential to control the increase in cancer prevalence. In the present work, we explored the role of cellular senescence barrier in the carcinogenic potential of some known carcinogens. We found that most carcinogens tested induce a primary senescent response in diploid mouse embryonic fibroblasts (MEFs) and the clones arising with proliferative capacity contain mutated p53 protein. This primary response of senescence induction is abolished in the presence of the p53 inhibitor, pifithrin-a. Under these conditions, the tumorigenic potential of carcinogens is greatly increased. Upon elimination of pifithrin-a from the media, cellular senescence is restored. Therefore, the first cellular response to a carcinogen is a cell cycle arrest program that may result in a permanent arrest with features of cellular senescence. If there is a concomitant alteration of genes involved in cellular senescence, which promotes cellular immortalization, a further carcinogenic insult may increase the chances of tumorigenesis and a malignant clone may develop.
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