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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Drug-Induced Expression of Nonsteroidal Anti-Inflammatory Drug-Activated Gene/Macrophage Inhibitory Cytokine-1/Prostate-Derived Factor, a Putative Tumor Suppressor, Inhibits Tumor Growth

Laboratories of Molecular Toxicology (J.M.M.) and Toxicology Operations Branch (N.J.W.) and Molecular Carcinogenesis (T.S., R.O., C.A., S.J.B., T.E.E.) National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina; SAIC-Frederick, Inc., Screening Technologies Branch, Laboratory of Functional Genomics, National Cancer Institute, Frederick, Maryland (M.H.,C.H., A.M.); National Decontamination Team, Office of Solid Waste and Emergency Response, Environmental Protection Agency, Cincinnati, Ohio (J.M.M.); Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee (S.J.B.); and Department of Radiation Biology and Health, School of Medicine, University of Occupational and Environmental Health Kitakyushu, Japan (R.O.)

A common in vitro response for many chemopreventive and antitumor agents, including some cyclooxygenase inhibitors, is the increased expression of nonsteroidal anti-inflammatory drug-activated gene (NAG)-1/macrophage inhibitory cytokine (MIC)-1/prostate-derived factor (PDF). The experimental anticancer drug 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F203) was a potent inducer of NAG-1 expression, and in MCF-7 cells, it inhibited cell growth and induced apoptosis. NAG-1 small interfering RNA blocked NAG-1 expression and 5F203-induced apoptosis in MCF-7 cells, indicating that NAG-1 may mediate the apoptosis and anticancer activity. One mechanism by which 5F203 increases NAG-1 expression is by increasing the stability of NAG-1 mRNA, dependent of de novo protein synthesis. Extracellular signal-regulated kinase (ERK) 1/2 phosphorylation was increased by 5F203, and inhibition of ERK1/2 phosphorylation abolished the induction of NAG-1 protein expression and increased the stability of NAG-1 mRNA. Thus, 5F203 regulates NAG-1 expression by a unique mechanism compared with other drugs. A mouse orthotopic mammary tumor model was used to determine whether 5F203 increased NAG-1 expression in vivo and suppressed tumor growth. Treatment of the mice with Phortress, the prodrug of 5F203, increased the in vivo expression of NAG-1 as measured by real-time reverse transcription-polymerase chain reaction from RNA obtained by needle biopsy, and the expression correlated with a reduction of tumor volume. These results confirm that NAG-1 suppresses tumor growth, and its in vivo expression can be controlled by treating mice with anticancer drugs, such as Phortress. Drugs that target NAG-1 could lead to a unique strategy for the development of chemotherapeutic and chemopreventive agents.

Address correspondence to: Dr. Thomas E. Eling, Laboratory of Molecular Carcinogenesis, 111 T.W. Alexander Dr., P.O. Box 12233, MD E4-09, Research Triangle Park, NC 27709. E-mail: eling{at}niehs.nih.gov

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