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Carcinogenesis Advance Access published online on July 29, 2004
Carcinogenesis, doi:10.1093/carcin/bgh245
© 2004 by Oxford University Press
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Received October 31, 2003
Revised June 24, 2004
Accepted July 21, 2004

CARCINOGENESIS

Mutant K-rasV12 increases COX-2, peroxides, and DNA damage in lung cells

Anna Maciag 1*, Gunamani Sithanandam 2, Lucy M. Anderson 1

1 Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick
2 Laboratory of Comparative Carcinogenesis, SAIC, NCI-Frederick

* To whom correspondence should be addressed. E-mail: amaciag{at}mail.ncifcrf.gov.


  Abstract

K-ras is frequently mutated in lung adenocarcinomas. Recent discovery that wild-type K-ras is tumor suppressive in lung raises a question: how is mutant K-ras aggressively oncogenic? We hypothesized that mutant K-ras might lead to generation of reactive oxygen species and DNA damage, contributing to malignant transformation. We stably transfected human mutant K-rasV12 into nontransformed peripheral mouse lung epithelial cells (E10 line). Constitutively active mutant K-rasV12 in E10 cells led to a highly significant (P<0.001) increased level of peroxides, and a corresponding increase in amount of DNA strand-break damage, compared with the parental line E10 and the vector control. Levels of superoxide were not increased, suggesting a direct source of peroxides, such as cyclooxygenase 2 (COX-2). COX-2 protein and activity measured as prostaglandin E2 level were up-regulated in cells expressing mutant K-rasV12; COX-2 activity correlated with K-ras activity (K-ras p21-GTP). Both peroxide generation and DNA single strand breaks were significantly reduced by pre-treatment with COX- 2 specific inhibitor SC 58125, confirming COX-2 as the source of the reactive oxygen species. COX-2 has been repeatedly implicated in lung cancer, and is known to be regulated by ras and to release reactive oxygen species. Our data suggests that upregulation of COX-2, with consequent increase in peroxides and DNA damage, contributes to the dominant oncogenicity of mutant K-ras.


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