5-Fluorouracil induces apoptosis through the suppression of NF-kappaB activity in human salivary gland cancer cells.
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.
Aota
K
K
Second Department of Oral and Maxillofacial Surgery, Tokushima University School of Dentistry, Tokushima, 770-8504, Japan.
Azuma
M
M
Yamashita
T
T
Tamatani
T
T
Motegi
K
K
Ishimaru
N
N
Hayashi
Y
Y
Sato
M
M
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D006868:Hydrolysis; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D012468:Salivary Gland Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D047992:TNF Receptor-Associated Factor 2; D051636:X-Linked Inhibitor of Apoptosis Protein; D019014:fas Receptor / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011506:Proteins; D047992:TNF Receptor-Associated Factor 2; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D019014:fas Receptor; D000072000:NF-KappaB Inhibitor alpha; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D005472:Fluorouracil