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Received for publication December 19, 2005.
Revised May 15, 2006.
Accepted for publication May 15, 2006.
A common in vitro response for many chemopreventive and antitumor agents, including some cyclooxygenase inhibitors, is the increased expression of NAG-1/MIC-1/PDF. The experimental anti-cancer drug 5F203 was a potent inducer of NAG-1 expression, and in MCF-7 cells, inhibited cell growth and induced apoptosis. NAG-1 siRNA blocked NAG-1 expression and 5F203 induced apoptosis in MCF-7 cells, indicating that NAG-1 may mediate the apoptosis and anti-cancer 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. ERK1/2 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 as compared to other drugs. A mouse orthotopic mammary tumor model was used to determine if 5F203 increased NAG-1 expression in vivo and suppressed tumor growth. Treatment of the mice with Phortress, the pro-drug of 5F203, increased the in vivo expression of NAG-1 as measured by real-time RT-PCR 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 anti-cancer drugs like Phortress. Drugs that target NAG-1 could lead to a unique strategy for the development of chemotherapeutic and chemopreventive agents.
Key words:
Cox inhibitors, NAG-1, NSAIDs, Phortress, anti-cancer, apoptosis
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