| Budget Amount *help |
¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2001: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2000: ¥1,000,000 (Direct Cost: ¥1,000,000)
|
|---|
| Research Abstract |
Recently, we reported that TNF/IFN-α combined treatment inhibited the in vitro and in vivo proliferation of human colon adenocarcinoma cells. Immunostaining and EMSA revealed that NF-κB was activated strongly by TNF/IFN-α compared to TNF alone in a human colon adenocarcinoma cell line, RPMI4788. Although inhibition of activated NF-κB, by using a NF-κB decoy, reduced cell viability after treatment with TNF only, NF-κB decoy resulted in recovery of cell viability after TNF/IFN-α treatment. Caspase-3 activity was increased in cells induced by TNF/IFN-α, while suppression of caspase-3 activity was observed in cells transfected with NF-κB decoy and then treated by TNF/IFN-α. On the other hand, Fas expression was strongly enhanced by TNF/IFN-α, and inhibition of TNF/IFN-α-induced NF-κB activation, by using NF-κB decoy, decreased Fas expression. Cell viability and caspase-3 activity decreased in cells treated with TNF/IFN-α and anti-FasL antibody. Taken together, our findings suggest that activated NF-κB induced by the cross-talk between TNF and IFN-α is a novel pro-apoptotic signal acting via enhancement of Fas expression. Our observations provide the first evidence in carcinoma cells indicating that TNF-induced NF-κB activation, which has an anti-apoptotic function, may be modified to a pro-apoptotic function by cytokine cross-talk between TNF and IFN-α. Such actions might be of clinicopharmacological value, where apoptosis of tumor cells could be efficiently induced by TNF/IFN-α and FasL, or up-regulators of FasL in combination might become a clinically applicable new strategy in cancer therapy.
|
