Effect of a mutant form of IkappaB-alpha on 5-fluorouracil-induced apoptosis in transformed human salivary gland cells.
Increasing evidence indicates that transcription factor NF-kappaB may play a role in cell survival, and that some chemotherapeutic agents activate NF-kappaB, while inhibition of NF-kappaB renders cells sensitive to these drugs. 5-Fluorouracil (5-FU) exerts its cytotoxic effect through the induction of apoptosis. However, it still remains uncertain whether 5-FU treatment in combination with the inhibition of NF-kappaB largely exerts an anti-proliferative effect on the growth of neoplastic human salivary gland cells. Thus, we investigated whether NF-kappaB suppression in transformed human salivary gland (NS-SV-AC) cells leads to a marked reduction in cell growth in response to 5-FU treatment. Our results demonstrated that under unstimulated conditions, the ability of cell growth in the super-repressor form of IkappaB-alpha (srIkappaB-alpha) cDNA-transfected cell clones (ACMT-6 and -7) was significantly lower than that in the empty vector-transfected cell clone (ACpRc-1). In addition, the growth inhibition caused by 5-FU was greatly enhanced in ACMT-6 and -7 as compared to ACpRc-1. Based on fractional inhibition analysis, this growth inhibition was due to an additive effect of both inhibitors. Electrophoretic mobility shift assay revealed that NF-kappaB activity in these cell clones was not affected by treatment with 5-FU. Accordingly, our data provide evidence that the combination of 5-FU and NF-kappaB suppression cooperatively functions in the growth inhibition of NS-SV-AC cells.
Motegi
K
K
Department of Oral and Maxillofacial Surgery 2, Tokushima University School of Dentistry, 3 Kuramoto-cho, Tokushima 770-8504, Japan.
Azuma
M
M
Aota
K
K
Yamashita
T
T
Tamatani
T
T
Harada
K
K
Yoshida
H
H
Sato
M
M
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002461:Cell Line, Transformed / Q000187:drug effects; D002999:Clone Cells / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005472:Fluorouracil / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins; D020287:In Situ Nick-End Labeling; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics; D012469:Salivary Glands / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D005472:Fluorouracil