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Activation of the Akt/Nuclear Factor-B Signaling Axis in Developing Lung Neoplasia^*

^* From the University of Cincinnati (Drs. Tichelaar and Anderson, and Mrs. Zhang), Cincinnati, OH; and the British Columbia Cancer Agency (Drs. LeRiche and Lam), Vancouver, BC, Canada.

Correspondence to: Jay W. Tichelaar, PhD, Department of Environmental Health, University of Cincinnati College of Medicine, 3223 Eden Ave, Cincinnati, OH 45267-0056; e-mail: Jay.Tichelaar{at}UC.edu

The lungs of smokers and former smokers typically contain multiple preneoplastic lesions that are at risk for developing into invasive cancer. Several chemopreventive agents are known to inhibit lung tumor formation and/or progression, but no single agent has proven to be completely effective at doses that can be readily extrapolated to humans. Combining agents that target distinct molecular pathways is one approach to identify treatments that effectively inhibit tumor cell growth or survival.

We have used the human lung adenocarcinoma cell line NCI-H441 to investigate the role of the chemopreventive agents budesonide, epi-gallocatechin gallate, and difluoromethyl ornithine in the Akt/nuclear factor (NF)-B pathway. Low doses of single agents that had little or no effect on the cells inhibited cell proliferation and NF-B reporter gene activity when used in combination. Levels of the active, phosphorylated form of Akt also were decreased by the combination treatment, correlating with the reduction in NF-B activity, while levels of total Akt were unchanged. We have subsequently examined the levels of the components of the Akt/NF-B pathway in human lung tumor biopsy samples. Increased levels of phospho-Akt, the NF-B subunit p65, and an NF-B target gene (cIAP-2) were observed in preneoplastic and neoplastic lesions.

These results indicate that the activation of the Akt/NF-B cell survival pathway occurs early during human lung tumorigenesis and that the inhibition of this pathway using combinations of chemopreventive agents may hold promise in the treatment of precancerous lesions in at-risk populations.

	Footnotes

 
Abbreviation: NF = nuclear factor

This Article Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Tichelaar, J. W. Articles by Anderson, M. W. Search for Related Content PubMed PubMed Citation Articles by Tichelaar, J. W. Articles by Anderson, M. W.