5-fluorouracil induces apoptosis through the suppression of NF-kappa B activity in human salivary gland cancer cells

Activation of the transcription factor NF-kappa B results in protection aga inst 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-kappa B activity. We found that upon treatment of a human salivary gland cancer cel l line (cl-1) with 5-FU, the NF-kappa B activity was suppressed in a time-d ependent manner. This inhibition was mediated by a prevention of the degrad ation of the inhibitory I kappa B-alpha protein. In addition, the expressio n of TRAF-2 and cIAP-1, which are transcriptionally regulated by NF-kappa B and function as anti-apoptotic molecules through the interruption of caspa se 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 cy tometric analysis, 5-FU did not affect the expression level of Fas on the c ell surface. Thus, our results suggest that one of the molecular mechanisms involved in B-FU-induced apoptosis in cl-l cells may be due to the suppres sion of NF-kappa B activity, resulting in the activation of the proapoptoti c pathway. (C) 2000 Academic Press.