Cyclooxygenase- and lipoxygenase-mediated DNA damage.
Cancer is a disease of aging, and so with the increasing age of the US population, the incidence of cancer is also increasing. Furthermore the global burden of cancer continues to increase largely because of aging and growth of the world population together with increasing smoking rates in economically developing countries. Tumor formation is critically dependent upon two processes--initiation and progression. The initiation step is mediated by DNA damage, which causes activating mutations in proto-oncogenes and inactivation of tumor suppressor genes in many cancers. This is then thought to facilitate tumor progression and metastasis. Cyclooxygenase-2 (COX-2) is upregulated at an early stage in tumorigenesis and has been implicated as an important mediator of proliferation through the increased formation of bioactive arachidonic acid (AA) metabolites such as prostaglandin E(2). Significantly, we have found that COX-2-mediated AA metabolism also results in the formation of heptanone-etheno (Hε)-DNA adducts. Furthermore, we showed that the Hε-DNA adducts arose from the reaction of DNA with the lipid hydroperoxide-derived bifunctional electrophile, 4-oxo-2(E)-nonenal (ONE). Similarly, 5-lipoxoygenase-mediated AA metabolism also results in the formation of ONE-derived DNA adducts. The resulting Hε-DNA adducts are highly mutagenic in mammalian cell lines suggesting that these pathways could be (in part) responsible for the somatic mutations observed in tumorigenesis. As approximately 80% of cancers arise from somatic mutations, this provides an additional link between the upregulation of COX-2 and tumorigenesis.
Centers for Cancer Pharmacology and Excellence in Environmental Toxicology, University of Pennsylvania Perelman School of Medicine, 854 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
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D000818:Animals; D018736:DNA Adducts / Q000378:metabolism*; D004260:DNA Repair; D006801:Humans; D015227:Lipid Peroxidation; D058945:Lipoxygenases / Q000378:metabolism*; D016296:Mutagenesis; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*
D018736:DNA Adducts; D058945:Lipoxygenases; D011451:Prostaglandin-Endoperoxide Synthases