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J. Biol. Chem., Vol. 281, Issue 34, 24182-24192, August 25, 2006

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Tumor Necrosis Factor Induces Spermidine/Spermine N¹-Acetyltransferase through Nuclear Factor Bin Non-small Cell Lung Cancer Cells^*

From the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231

Tumor necrosis factor (TNF) is a potent pleiotropic cytokine produced by many cells in response to inflammatory stress. The molecular mechanisms responsible for the multiple biological activities of TNF are due to its ability to activate multiple signal transduction pathways, including nuclear factor B (NFB), which plays critical roles in cell proliferation and survival. TNF displays both apoptotic and antiapoptotic properties, depending on the nature of the stimulus and the activation status of certain signaling pathways. Here we show that TNF can lead to the induction of NFB signaling with a concomitant increase in spermidine/spermine N¹-acetyltransferase (SSAT) expression in A549 and H157 non-small cell lung cancer cells. Induction of SSAT, a stress-inducible gene that encodes a rate-limiting polyamine catabolic enzyme, leads to lower intracellular polyamine contents and has been associated with decreased cell growth and increased apoptosis. Stable overexpression of a mutant, dominant negative IB protein led to the suppression of SSAT induction by TNF in these cells, thereby substantiating a role of NFB in the induction of SSAT by TNF. SSAT promoter deletion constructs led to the identification of three potential NFB response elements in the SSAT gene. Electromobility shift assays, chromatin immunoprecipitation experiments and mutational studies confirmed that two of the three NFB response elements play an important role in the regulation of SSAT in response to TNF. The results of these studies indicate that a common mediator of inflammation can lead to the induction of SSAT expression by activating the NFB signaling pathway in non-small cell lung cancer cells.

Received for publication, February 27, 2006 , and in revised form, May 16, 2006.

^* The research was supported by National Institutes of Health Grants CA 51085 and CA 98454. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21231. Tel.: 410-955-8580; Fax: 410-614-9884; E-mail: rcasero{at}jhmi.edu.

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