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Carcinogenesis Advance Access originally published online on July 29, 2004
Carcinogenesis 2004 25(11):2231-2237; doi:10.1093/carcin/bgh245
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Carcinogenesis vol.25 no.11 © Oxford University Press 2004; all rights reserved.

ARTICLE

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

Anna Maciag1,3, Gunamani Sithanandam2 and Lucy M. Anderson1

1 Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick and 2 Basic Research Program SAIC-Frederick, Inc., Frederick, MD 21702, USA

3 To whom correspondence should be addressed Email: amaciag{at}mail.ncifcrf.gov

K-ras is frequently mutated in lung adenocarcinomas. Recent discovery that wild-type K-ras is tumor suppressive in the 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 (ROS) and DNA damage, contributing to malignant transformation. We stably transfected human mutant K-rasV12 into non-transformed 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 the 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 ROS. COX-2 has been repeatedly implicated in lung cancer, and is known to be regulated by ras and to release ROS. Our data suggest that up-regulation of COX-2, with a consequent increase in peroxides and DNA damage, contributes to the dominant oncogenicity of mutant K-ras.


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