Nuclear factor-κB dependency of doxorubicin sensitivity in gastric cancer cells is determined by manganese superoxide dismutase expression

The role of nuclear factor-kappa B (NF-kappa B) activation in cancer cell apoptosis appears to be tailored specifically for each cell type and the type of NF-kappa B inducer. The present study aimed to determine whether or not NF-kappa B activation is associated with chemosensitivity to doxorubicin (DOX) using the DOX-sensitive SNU-601 and DOX-resistant SNU-216 gastric cancer cell lines. The effect of NF-kappa B activation on DOX (1 mu g/mL) sensitivity was analyzed after the suppression of NF-kappa B activation using transfection of the super-suppressive mutant form of I kappa B alpha (mI kappa B alpha) or pretreatment with pyrrolidine dithiocarbamate. In addition, the association between NF-kappa B and manganese superoxide dismutase (MnSOD) in relation to DOX sensitivity was analyzed after the modulation of MnSOD expression. The NF-kappa B activity was much higher in DOX-resistant SNU-216 cells than in DOX-sensitive SNU-601 cells before and after DOX treatment. Overexpression of mI kappa B alpha or pyrrolidine dithiocarbamate pretreatment decreased the DOX resistance in SNU-601 cells with low MnSOD expression, but not in SNU-216 cells with high MnSOD expression. In comparison, the overexpression of MnSOD, which also suppressed NF-kappa B activation in both cell lines, increased DOX resistance in SNU-601 cells. Blocking of MnSOD expression using RNA interference techniques increased DOX sensitivity in SNU-216 cells, which was further augmented by the additional inhibition of NF-kappa B activity. Our results showed that whether NF-kappa B contributes to DOX sensitivity in gastric cancer cells is determined by the level of MnSOD expression. Thus, targeting both MnSOD and NF-kappa B may be helpful for increasing the efficacy of DOX treatment of DOX-resistant SNU gastric cancer cells.