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United States Department of Agriculture

Agricultural Research Service

Title: 9-Cis Retinoic Acid Inhibition of Lung Carcinogenesis in the A/j Mouse Model Is Accompanied by Increased Expression of Rar-Beta But No Change in Cyclooxygenase-2

Authors
item Mernitz, Heather - TUFTS/HNRCA
item Smith, Donald - TUFTS/HNRCA
item Zhu, Andrew - HARVARD-MASS GENL HOSP
item Wang, Xiang-Dong

Submitted to: Cancer Letters
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: December 14, 2005
Publication Date: December 8, 2006
Citation: Mernitz, H., Smith, D.E., Zhu, A.X., Wang, X. 2006. 9-cis retinoic acid inhibition of lung carcinogenesis in the a/j mouse model is accompanied by increased expression of rar-beta but no change in cyclooxygenase-2. Cancer Letters. 244(1):101-108.

Interpretive Summary: 9-Cis-retinoic acid (9cRA) is a unique form of vitamin A that has been shown to inhibit lung cancer cell growth and to act as a potential cancer prevention agent in human studies of former smokers by restoring levels of retinoic acid receptor-beta, a protein whose loss is considered a biomarker for lung cancer. However, there is currently no direct evidence of the efficacy of 9cRA against lung tumor development in a living system. Further, the mechanism by which 9cRA protects against lung cancer remains largely unknown. In this study, we show that 9cRA is effective in decreasing prevalence of tumors in a mouse model of lung cancer at a dose that causes no weight-loss associated toxicity or mortality. In comparison, treatment with celecoxib, an anti-inflammatory drug known to inhibit lung cancer in this animal model, caused 29% mortality due to gastrointestinal bleeding. Investigations into the mechanism behind the effectiveness of this form of vitamin A against lung cancer showed that 9cRA treatment did increase expression of retinoic acid receptor-beta. However, this increase was not accompanied by decreased mRNA or protein levels of cyclooxygenase-2, an inflammatory protein often elevated in lung and other cancers.

Technical Abstract: 9-Cis-retinoic acid (9cRA) binds both retinoic acid receptors (RARs) and retinoid X receptors (RXRs) and has been shown to be a potential chemopreventive agent both in lung cancer cell culture studies and in clinical trials studying former smokers. However, direct evidence of the efficacy of 9cRA against lung tumor development in vivo is lacking. In the present study, we determined whether treatment with 9cRA has the potential to inhibit lung carcinogenesis by upregulating RAR-beta and down-regulating COX-2 expression in the A/J mouse lung cancer model. A/J mice (n=14-15/group) were treated as follows: 1) Control (Sham treated); 2) NNK (100 mg NNK/kg body weight); 3) NNK + 9cRA (15 mg/kg diet); and 4) NNK + celecoxib (a COX-2-specific inhibitor, 500 mg/kg diet). Tumor incidence, tumor multiplicity, RAR-beta mRNA, COX-2 mRNA, and COX-2 protein levels in lung samples of mice were determined four months after carcinogen injection. The results showed that mice receiving 9cRA supplementation had significantly lower tumor multiplicity (48% reduction, p<0.05) and showed a trend toward lower tumor incidence (40% reduction, p=0.078), as compared with the mice given NNK alone. Although celecoxib treatment resulted in greater declines in tumor incidence and tumor multiplicity (75% and 88%, respectively, p<0.05), the chemoprotective effects of celecoxib were accompanied by increased mortality while 9cRA treatment resulted in no weight-loss associated toxicity or mortality. Supplementation with 9cRA was effective in increasing RAR-beta mRNA, but this increase was not accompanied by decreased levels of COX-2 mRNA or protein. These results suggest that 9cRA supplementation may provide protection against lung carcinogenesis and this effect may be mediated in part by 9cRA induction of RAR-beta, but not inhibition of COX-2 transcription.

Last Modified: 4/18/2014
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