The Biology and Regulation of Activating Transcription Factor 3 (ATF3) by Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and Dietary Compounds with Chemopreventive Activity.

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Title: The Biology and Regulation of Activating Transcription Factor 3 (ATF3) by Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and Dietary Compounds with Chemopreventive Activity.
Author: Bottone, Frank Gerard Jr.
Advisors: Thomas E. Eling, Committee Co-Chair
Jack Odle, Committee Member
Jonathan Allen, Committee Member
Brenda Alston-Mills, Committee Co-Chair
Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective chemopreventive agents in various tissue types such as colon and breast. Until recently their mode of action was thought to be solely through inhibition of cyclooxygenase-2 (Cox-2), which along with its products such as prostaglandin E2, are upregulated in tumors. However, gene regulation may, in part, explain the alterations in invasion, apoptosis, and/or cell proliferation seen with NSAIDs. In this report, we utilized microarray analysis of colorectal cancer cells treated with low, non-toxic concentrations of sulindac sulfide to show that the active metabolite of this NSAID and potent cancer chemopreventive drug regulates the expression of a variety of genes. Several genes related to cell growth and apoptosis, while others were transcription factors, which are important regulators of gene expression. NSAIDs such as the Cox-1 specific inhibitor SC-560 and the Cox-2 specific inhibitor SC-58125 modulated the expression of these genes in HCT-116 colorectal cancer cells, which correlated with the biological activity but not Cox-2 inhibitory activity of these compounds. Activating Transcription Factor 3 (ATF3) was one gene identified as induced by a variety of NSAIDs and confirmed in a variety of cell lines in our laboratory. ATF3 was induced by a variety of other compounds with cancer chemopreventive activity such as the PPAR gamma ligand troglitazone (TGZ) and the dietary compounds diallyl disulfide (DADS), resveratrol, and genistein. To ascertain the biological significance of the induction of ATF3, we overexpressed ATF3 in the sense and antisense orientation. Overexpression of ATF3 in the sense orientation reduced the size of mouse tumor xenografts by 54 percent in vivo. One explanation for the biological activity of ATF3 is down-stream gene modulation. Using microarray analysis, overexpression of ATF3 in the sense orientation regulated several genes related to invasion and metastasis. ATF3 overexpression decreased focus formation and inhibited invasion potential in vitro to a similar degree as sulindac sulfide treatment. Conversely, antisense ATF3 overexpression increased invasion potential and focus formation. Therefore, the biological activity of these compounds may be linked to the gene regulator role of ATF3. Lastly, we demonstrated that ATF3 is modulated by the transcription factor Early Growth Response Gene-1 (Egr-1). The induction of ATF3 by sulindac sulfide and TGZ at the mRNA, protein, and promoter level required Egr-1 and the Extracellular regulated kinase-1/2 (Erk-1/2) MAPK pathway. In conclusion, NSAIDs and other chemopreventive compounds alter the expression of a number of genes, in particular transcription factors, which may be linked to the biological activity of these compounds. Lastly, we dispute the dogma that ATF3 is solely a stress response gene and provide evidence that ATF3 has anti-cancer activity warranting further investigation.
Date: 2005-04-19
Degree: PhD
Discipline: Nutrition

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