Tumor necrosis factor alpha induces spermidine/spermine N1-acetyltransferase through nuclear factor kappaB in non-small cell lung cancer cells.

Full 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.

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Author information

Author/s: Babbar, Naveen (N); Hacker, Amy (A); Huang, Yi (Y); Casero, Robert A (RA);

Affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.

Grants: CA 51085 (Agency:NCI NIH HHS) ; CA 98454 (Agency:NCI NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural

Journal: The Journal of biological chemistry (J Biol Chem), published in United States. (Language: eng)

Reference: 2006-Aug; vol 281 (issue 34) : pp 24182-92

Dates: Created 2006/08/21; Completed 2006/11/06; Revised 2008/11/21;

PMID: 16757480, status: MEDLINE (last retrieval date: 12/26/2008)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Acetyltransferases - biosynthesis; genetics
Carcinoma, Non-Small-Cell Lung - genetics; metabolism
Cell Line, Tumor
Enzyme Induction - drug effects
Gene Expression Regulation, Enzymologic - drug effects
Gene Expression Regulation, Neoplastic - drug effects
Humans
Inflammation - metabolism

Lung Neoplasms - genetics; metabolism
NF-kappa B - metabolism
Paclitaxel - pharmacology
Polyamines - metabolism
Promoter Regions, Genetic
Recombinant Proteins - metabolism; pharmacology
Signal Transduction - drug effects; genetics
Tumor Necrosis Factor-alpha - metabolism; pharmacology

Associated Chemicals: NF-kappa B (0) ; Polyamines (0) ; Recombinant Proteins (0) ; Tumor Necrosis Factor-alpha (0) ; Paclitaxel (33069-62-4) ; Acetyltransferases (EC 2.3.1.-) ; diamine N-acetyltransferase (EC 2.3.1.57)

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