5-Fluorouracil suppression of NF-KappaB is mediated by the inhibition of IKappab kinase activity in human salivary gland cancer cells.

Abstract

We have recently shown that 5-Fluorouracil (5-FU) suppresses the transcription factor NF-kappaB in human salivary gland cancer cells (cl-1) by mediating upregulation of IkappaB-alpha expression. However, the precise mechanism involved in this action has not yet been elucidated. IkappaB kinases (IKK-alpha and IKK-beta) are the key components of the IKK complex that mediates activation of NF-kappaB in response to external stimuli such as cytokines. In addition, NF-kappaB-inducing kinase (NIK) and mitogen-activated protein kinase kinase kinase 1 (MEKK-1), both of which are the upstream kinases for the IKKs, interact with and activate the IKKs. Thus, we investigated the molecular mechanisms involved in the suppression of NF-kappaB by 5-FU. Although 5-FU did not affect the expression levels of IKKs, NIK, or MEKK-1, IKK activity in cl-1 cells was suppressed at both 6 h and 12 h after treatment with 2 microgram/ml 5-FU. Moreover, when cells were treated with various concentrations of 5-FU for 12 h, the concentration of 2 microgram/ml efficiently inhibited the IKK activity as compared to 1, 5, or 10 microgram/ml. The expression of Fas-associated death domain-like interleukin 1-converting enzyme-inhibitory protein (FLIP), which acts as an inhibitor of an initiator caspase (caspase-8), was down-regulated by 5-FU treatment in cl-1 cells. Apoptosis, as evidenced by cleavage of poly(ADP-ribose) polymerase through the action of an executioner caspase (caspase-3), was also clearly observed. Thus, these results suggest that 5-FU induction of apoptosis in cl-1 cells may be mediated by suppression of NF-kappaB via inhibition of IKK activity.

• Authors: M Azuma, T Yamashita, K Aota, T Tamatani, M Sato
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 282 Issue 1 Pg. 292-6 (Mar 23 2001) ISSN: 0006-291X [Print] United States
• PMID: 11264006 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2001 Academic Press.

Chemical References

• NF-kappa B
• Poly(ADP-ribose) Polymerases
• Protein Serine-Threonine Kinases
• CHUK protein, human
• I-kappa B Kinase
• IKBKB protein, human
• IKBKE protein, human
• MAP Kinase Kinase Kinase 1
• MAP3K1 protein, human
• NF-kappa B kinase
• Fluorouracil

Topics

• Fluorouracil (pharmacology)
• Humans
• Hydrolysis
• I-kappa B Kinase
• MAP Kinase Kinase Kinase 1
• NF-kappa B (antagonists & inhibitors)
• Poly(ADP-ribose) Polymerases (metabolism)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Salivary Gland Neoplasms (enzymology, metabolism, pathology)