Abstract
Tumor necrosis factor alpha (TNFalpha) is a potent pleiotropic cytokine produced by many cells in response to inflammatory stress. The molecular mechanisms responsible for the multiple biological activities of TNFalpha are due to its ability to activate multiple signal transduction pathways, including nuclear factor kappaB (NFkappaB), which plays critical roles in cell proliferation and survival. TNFalpha 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 TNFalpha can lead to the induction of NFkappaB signaling with a concomitant increase in spermidine/spermine N(1)-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 IkappaBalpha protein led to the suppression of SSAT induction by TNFalpha in these cells, thereby substantiating a role of NFkappaB in the induction of SSAT by TNFalpha. SSAT promoter deletion constructs led to the identification of three potential NFkappaB response elements in the SSAT gene. Electromobility shift assays, chromatin immunoprecipitation experiments and mutational studies confirmed that two of the three NFkappaB response elements play an important role in the regulation of SSAT in response to TNFalpha. The results of these studies indicate that a common mediator of inflammation can lead to the induction of SSAT expression by activating the NFkappaB signaling pathway in non-small cell lung cancer cells.
Highlights
The transfer of the acetyl group from acetyl-CoA to the N1 position of spermidine or spermine and has a predominant role in the regulation of intracellular polyamine concentrations in mammalian cells [1, 2]
We examined the effects of TNF␣ treatment on spermidine/spermine N1-acetyltransferase (SSAT) expression in representative human non-small cell lung cancer cells and identified the specific nuclear factor B (NFB) response elements responsible for the regulation of SSAT by TNF␣
Since SSAT has been implicated as a stress response gene [1], we sought to determine whether TNF␣, acting through NFB, altered the expression of SSAT in the Non-small Cell Lung Cancer (NSCLC) cells
Summary
The transfer of the acetyl group from acetyl-CoA to the N1 position of spermidine or spermine and has a predominant role in the regulation of intracellular polyamine concentrations in mammalian cells [1, 2]. We have shown that aspirin can induce SSAT expression in colon cancer cells, partly by activating the NFB signaling pathway, which leads to the binding of NFB complexes to the NFB response elements in the SSAT 5Ј promoter region [19].
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