Elevated NF-κB responses and FLIP levels in leukemic but not normal lymphocytes: reduction by salicylate allows TNF-induced apoptosis

Colin Rae, Susana Langa, Steven John Tucker, David Joseph MacEwan

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

As its name suggests, tumor necrosis factor (TNF) is known to induce cytotoxicity in a wide variety of tumor cells and cell lines. However, its use as a chemotherapeutic drug has been limited by its deleterious side effects of systemic shock and widespread inflammatory responses. Some nonsteroidal antiinflammatory drugs, such as sodium salicylate, have been shown to have a chemopreventive role in certain forms of cancer. Here, we reveal that sodium salicylate selectively enhances the apoptotic effects of TNF in human erythroleukemia cells but does not affect primary human lymphocytes or monocytes. Sodium salicylate did not affect the intracellular distribution of TNF receptors (TNFRs) but stimulated cell surface TNFR2 shedding. Erythroleukemia cells were shown to possess markedly greater basal NF-κB responses and elevated Fas-associated protein with death domain-like IL-1converting enzyme (FLIP) levels. Sodium salicylate achieved its effects by reducing the elevated NF-κB responsiveness and FLIP levels and restoring the apoptotic response of TNF rather than the proliferative/proinflammatory effects of the cytokine in these cancer cells. Inhibition of NF-κB or FLIP levels in human erythroleukemia cells by pharmacological or molecular-biological means also resulted in switching the character of these cells from a TNF-responsive proliferative phenotype into an apoptotic one. These findings expose that the enhanced proliferative nature of human leukemia cells is caused by elevated NF-κB and FLIP responses and basal levels, reversible by sodium salicylate to allow greater apoptotic responsiveness of cytotoxic stimuli such as TNF. Such findings provide insight into the molecular mechanisms by which human leukemia cells can switch from a proliferative into an apoptotic phenotype.
Original languageEnglish
Pages (from-to)12790-12795
Number of pages6
JournalPNAS
Volume104
Issue number31
Early online date24 Jul 2007
DOIs
Publication statusPublished - 31 Jul 2007

Fingerprint

Salicylates
Tumor Necrosis Factor-alpha
Sodium Salicylate
Lymphocytes
Apoptosis
Leukemia, Erythroblastic, Acute
Leukemia
Fas-Associated Death Domain Protein
Receptors, Tumor Necrosis Factor, Type II
Phenotype
Neoplasms
Tumor Necrosis Factor Receptors
Pharmaceutical Preparations
Names
Monocytes
Shock
Anti-Inflammatory Agents
Pharmacology
Cytokines
Cell Line

Keywords

  • cancer cells
  • cytokine
  • receptor
  • sodium salicylate
  • leukemia

Cite this

Elevated NF-κB responses and FLIP levels in leukemic but not normal lymphocytes : reduction by salicylate allows TNF-induced apoptosis. / Rae, Colin; Langa, Susana; Tucker, Steven John; MacEwan, David Joseph.

In: PNAS, Vol. 104, No. 31, 31.07.2007, p. 12790-12795.

Research output: Contribution to journalArticle

Rae, Colin ; Langa, Susana ; Tucker, Steven John ; MacEwan, David Joseph. / Elevated NF-κB responses and FLIP levels in leukemic but not normal lymphocytes : reduction by salicylate allows TNF-induced apoptosis. In: PNAS. 2007 ; Vol. 104, No. 31. pp. 12790-12795.
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