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

Mutant K-rasV12 increases COX-2, peroxides and DNA damage in lung cells. Research Abstract Details 

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Mutant K-rasV12 increases COX-2, peroxides and DNA damage in lung cells. Abstract Text:

Anna Maciag,Gunamani Sithanandam,Lucy M Anderson,

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-ras(V12) into non-transformed peripheral mouse lung epithelial cells (E10 line). Constitutively active mutant K-ras(V12) 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 E(2) level were up-regulated in cells expressing mutant K-ras(V12); 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.

Mutant K-rasV12 increases COX-2, peroxides and DNA damage in lung cells. Publishing Authors By Initials

A Maciag,G Sithanandam,LM Anderson,

For similar inorganic chemicals: electrolytes: ions: anions: oxides: peroxides: superoxides research abstracts see: inorganic chemicals: electrolytes: ions: anions: oxides: peroxides: superoxides research

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Mutant K-rasV12 increases COX-2, peroxides and DNA damage in lung cells. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Carcinogenesis

VOLUME: 25

Page Numbers: 2231-7

Journal Abbreviation: Carcinogenesis

ISSN: 0143-3334

DAY: 29

MONTH: 07

YEAR: 2004

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

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LANGUAGE: eng

NlmUniqueID: 8008055

Mutant K-rasV12 increases COX-2, peroxides and DNA damage in lung cells. Keywords Mesh Terms:

KEYWORDS: Superoxides

MESH TERMS: metabolism

Chemical & Substance for Abstract: Mutant K-rasV12 increases COX-2, peroxides and DNA damage in lung cells. Information

Substance Name: PTGS2 protein, human

Registry Number: EC 1.14.99.1

Grant and Affiliation Information for Mutant K-rasV12 increases COX-2, peroxides and DNA damage in lung cells.

AFFILIATION: Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Inc., Frederick, MD 21702, USA. amaciag@mail.ncifcrf.gov

Country: England

AGENCY: United States NCI

GRANT: NC-CO-12400

ACRONYM: CO

MEDLINETA: Carcinogenesis

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