NF-κB is pleiotrophic transcription factor which functions in regulation of cell proliferation, apoptosis, embryonic development, tumorigenesis, immuno and inflammatory responses. The anti- or pro-apoptotic function of NF-κB is dependent on the cell type and stimuli. In our previous studies, we found that doxycycline-mediated superoxide generation induced p53 phosphorylation and apoptosis was dependent on NF-κB activation. We hypothesize that PLK3, a kinase that phosphorylate p53 on Ser-20 in response to DNA damage, is regulated by NF-κB. The doxycycline-treatment of pancreatic cancer cell line MDAPanc28 resulted in the activation of NF-κB and the induction of PLK3 expression. Mutant IκBα (IκBαM) mediated inhibition of NF-κB activation down-regulated PLK3 expression, indicating that induction of PLK3 expression by doxycycline depended on NF-κB activation. Our study revealed that PLK3 promoter has an NF-κB binding site and it is responsible for NF-κB-dependent induction of PLK3 by doxycycline. Our results showed that downregulation of PLK3 expression by siRNA inhibited the doxycycline-inducible phosphorylation of p53. Taken together, these data suggest that in response to doxycycline stimulation, NF-κB induced expression of PLK3, which in turn activates p53-dependent and independent cell-growth inhibition and apoptosis signaling cascades.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]