| Budget Amount *help |
¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 1999: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1998: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Research Abstract |
1. We have recently demonstrated that growing human salivary gland cells express relatively large amounts of p50/p65 complexes at the basal level (Azuma, M., Lab. Invest 77 : 269-280, 1997), possibly implying that the NF-κB activity might be important in the proliferation of human salivary gland cells. Indeed, several lines of evidence suggest that NF-κB activity contributes to the expression of the neoplastic phenotype or malignant progression in certain cell types. We found that TGF-β1 treatment of salivary gland cells showed the inhibition of the NF-κB activity. This inhibition could be related, in part to elevated levels of lκB-α mRNA and protein resulting from increased transcription of the lκB-α gene. Antisense inhibition of the NF-κB complex reduced the proliferation of the cell clones. Moreover, expression of the super-repressor form of lκB-α in a cell clone decreased the growth rate of this cell clone. Therefore, these results indicate that induction of lκB-α expression by TGF
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-β1 suppresses the growth of human salivary gland cells by the inhibition of NF-κB activity, which regulates the genes involved in cell proliferation.
2. We investigated whether NF-κB 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 lκB-α (srlκB-α) cDNA-transfected cell clones (ACMT-6 and ACMT-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 ACMT-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-κB 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-κB suppression cooperatively functions in the growth inhibition of NS-SV-AC cells. Less
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