Tumor necrosis factor α induces spermidine/spermine N 1-acetyltransferase through nuclear factor κB in non-small cell lung cancer cells

Naveen Babbar, Amy Hacker, Yi Huang, Robert A. Casero

Research output: Contribution to journalArticle

Abstract

Tumor necrosis factor α (TNFα) is a potent pleiotropic cytokine produced by many cells in response to inflammatory stress. The molecular mechanisms responsible for the multiple biological activities of TNFα are due to its ability to activate multiple signal transduction pathways, including nuclear factor κB (NFκB), which plays critical roles in cell proliferation and survival. TNFκ 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 TNFα can lead to the induction of NFκB 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 IκBα protein led to the suppression of SSAT induction by TNFα in these cells, thereby substantiating a role of NFκB in the induction of SSAT by TNFα. SSAT promoter deletion constructs led to the identification of three potential NFκB response elements in the SSAT gene. Electromobility shift assays, chromatin immunoprecipitation experiments and mutational studies confirmed that two of the three NFκB response elements play an important role in the regulation of SSAT in response to TNFα. The results of these studies indicate that a common mediator of inflammation can lead to the induction of SSAT expression by activating the NFκB signaling pathway in non-small cell lung cancer cells.

Original languageEnglish (US)
Pages (from-to)24182-24192
Number of pages11
JournalJournal of Biological Chemistry
Volume281
Issue number34
DOIs
StatePublished - Aug 25 2006

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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