5-Fluorouracil induces apoptosis through the suppression of NF-kappaB activity in human salivary gland cancer cells.

Abstract

Activation of the transcription factor NF-kappaB results in protection against apoptosis, and the chemotherapeutic agent 5-Fluorouracil (5-FU) exerts its cytotoxic effect through the induction of apoptosis. Thus, we examined whether 5-FU could induce apoptosis through the suppression of NF-kappaB activity. We found that upon treatment of a human salivary gland cancer cell line (cl-1) with 5-FU, the NF-kappaB activity was suppressed in a time-dependent manner. This inhibition was mediated by a prevention of the degradation of the inhibitory IkappaB-alpha protein. In addition, the expression of TRAF-2 and cIAP-1, which are transcriptionally regulated by NF-kappaB and function as anti-apoptotic molecules through the interruption of caspase pathway, was also inhibited by 5-FU. Finally, the activity of caspase-8 and caspase-3 showed a significant increase in response to 5-FU. By flow cytometric analysis, 5-FU did not affect the expression level of Fas on the cell surface. Thus, our results suggest that one of the molecular mechanisms involved in 5-FU-induced apoptosis in cl-1 cells may be due to the suppression of NF-kappaB activity, resulting in the activation of the pro-apoptotic pathway.

• Authors: K Aota, M Azuma, T Yamashita, T Tamatani, K Motegi, N Ishimaru, Y Hayashi, M Sato
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 273 Issue 3 Pg. 1168-74 (Jul 14 2000) ISSN: 0006-291X [Print] United States
• PMID: 10891390 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2000 Academic Press.

Chemical References

• Antimetabolites, Antineoplastic
• DNA-Binding Proteins
• I-kappa B Proteins
• NF-kappa B
• NFKBIA protein, human
• Proteins
• TNF Receptor-Associated Factor 2
• X-Linked Inhibitor of Apoptosis Protein
• XIAP protein, human
• fas Receptor
• NF-KappaB Inhibitor alpha
• CASP3 protein, human
• CASP8 protein, human
• CASP9 protein, human
• Caspase 3
• Caspase 8
• Caspase 9
• Caspases
• Fluorouracil

Topics

• Antimetabolites, Antineoplastic (pharmacology)
• Apoptosis (drug effects)
• Caspase 3
• Caspase 8
• Caspase 9
• Caspases (metabolism)
• Cell Division (drug effects)
• DNA-Binding Proteins (metabolism)
• Enzyme Activation
• Fluorouracil (pharmacology)
• Humans
• Hydrolysis
• I-kappa B Proteins
• NF-KappaB Inhibitor alpha
• NF-kappa B (antagonists & inhibitors, metabolism)
• Proteins (metabolism)
• Salivary Gland Neoplasms (enzymology, metabolism, pathology)
• TNF Receptor-Associated Factor 2
• X-Linked Inhibitor of Apoptosis Protein
• fas Receptor (metabolism)