Document Detail

Cyclooxygenase- and lipoxygenase-mediated DNA damage.
MedLine Citation:
PMID:  22009064     Owner:  NLM     Status:  MEDLINE    
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.
N Speed; I A Blair
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Review    
Journal Detail:
Title:  Cancer metastasis reviews     Volume:  30     ISSN:  1573-7233     ISO Abbreviation:  Cancer Metastasis Rev.     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-14     Completed Date:  2012-04-02     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  8605731     Medline TA:  Cancer Metastasis Rev     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  437-47     Citation Subset:  IM    
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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MeSH Terms
DNA Adducts / metabolism*
DNA Repair
Lipid Peroxidation
Lipoxygenases / metabolism*
Neoplasms / enzymology,  genetics,  metabolism
Oxidative Stress
Prostaglandin-Endoperoxide Synthases / metabolism*
Grant Support
Reg. No./Substance:
0/DNA Adducts; EC 1.13.11.-/Lipoxygenases; EC Synthases

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