Induction of Apoptosis of Cytokine-Producing Bladder Cancer Cells by Adenovirus-Mediated I kappa B alpha Overexpression

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Abstract
We investigated whether the cell growth and apoptosis of multiple cytokine-producing bladder cancer cells can be regulated by nuclear factor kappa B (NF-kappa B). The bladder cancer cell line KU-19-19, obtained from a 76- year-old man who demonstrated marked leukocytosis, produces multiple cytokines and demonstrates autocrine growth by granulocyte colony-stimulating factor (G-CSF). Electrophoretic mobility shift assay (EMSA) re- vealed that NF-kappa B was activated in KU-19-19 but not in other bladder cancer cell lines (KU-1, KU-7, or T- 24, respectively). The inhibition of NF-kappa B DNA-binding activity with adenovirus vectors expressing the sta- ble form of the NF-kappa B inhibitor I kappa B alpha (multiplicity of infection [MOI] of 10) inhibited growth and induced apoptosis of KU-19-19, but not KU-1, KU-7, or T-24. The production of several cytokines was suppressed sig- nificantly in KU-19-19 by this gene delivery. Although dexamethasone (10 mu M) could also suppress cytokine production, it did not induce dramatic cell death in KU-19-19 because it could not inhibit NF- kappa B activation stably and strongly. These results suggest that NF- kappa B activation maintains the cell viability as well as regu- lates cytokine production in cytokine-producing cancer cells and therefore these in vitro experiments support a rationale for preclinical in vivo studies to demonstrate growth inhibition in established tumors.