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Carcinogenesis Advance Access published online on March 14, 2007
Carcinogenesis, doi:10.1093/carcin/bgm056
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Published by Oxford University Press 2007.

Modulation by Budesonide of a CpG Endonuclease in Mouse Lung Tumors

Long Li1,4, Lianhui Tao2, Ronald A. Lubet3, Vernon E. Steele3 and Michael A. Pereira1,2

1 Department of Biochemistry and Cancer Biology, Medical University of Ohio, 3055 Arlington Avenue, Toledo, Ohio 43614-5806, USA
2 Division of Hematology and Oncology, Department of Internal Medicine, College of Medicine, Ohio State University, 1148 CHRI, 300 W 10th Avenue, Columbus, Ohio 43210-1240, USA
3 Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland 20892, USA
4 Present Address: Division of Biology, California Institute of Technology, Mail Code 156-29, 1200 E. California Boulevard, Pasadena, California 91125, USA

Corresponding Author: Dr. Michael A. Pereira, Division of Hematology and Oncology, Department of Internal Medicine, College of Medicine, Ohio State University, 1148 CHRI, 300 W 10th Avenue, Columbus, Ohio 43210-1240, USA. (Tel) 614-293-6864, E-mail: michael.pereira{at}osumc.edu

CpG endonuclease activity was identified in nuclear extracts obtained from mouse lung tumors. Enzyme activity was determined using a 333bp PCR-Product of the estrogen receptor-{alpha} gene that contained either radiolabeled cytosine or tritium-labeled methyl groups at CpG sites. Activity was measured as the release of radioactivity from the substrate. The product of the nuclease activity was identified by HPLC as either 5-methyl-2'-deoxycytidine when the CpG sites in the substrate were methylated or 2'-deoxycytidine when the CpG sites were not methylated. The CpG endonuclease activity was dependent on nuclear protein and temperature, had a proclivity for double stranded over single stranded DNA, and was inhibited by EDTA or 2-mercaptoethanol. Strain A/J mouse lung tumors induced by vinyl carbamate had a greater level of CpG endonuclease activity than non-involved lung tissue. Budesonide, a potent chemopreventive agent in mouse lung, not only prevented an increase in CpG endonuclease activity in lung tumors, but when administered to mice with established tumors, it also decreased the level of endonuclease activity in the tumors. The effect of budesonide on CpG endonuclease activity in lung tumors was inversely related to its published effect on DNA methylation in mouse lung tumors, i.e. the drug decreased CpG endonuclease activity and increased the methylation of DNA. The increased CpG endonuclease activity in mouse lung tumors and its inhibition by budesonide, would suggest this endonuclease as a potential molecular target for chemoprevention.

Received November 8, 2006; revised February 23, 2007; accepted March 1, 2007.


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