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

The role of nuclear factor‐κB (NF‐κB) activation in cancer cell apoptosis appears to be tailored specifically for each cell type and the type of NF‐κB inducer. The present study aimed to determine whether or not NF‐κB 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‐κB activation on DOX (1 µg/mL) sensitivity was analyzed after the suppression of NF‐κB activation using transfection of the super‐suppressive mutant form of IκBα (mIκBα) or pretreatment with pyrrolidine dithiocarbamate. In addition, the association between NF‐κB and manganese superoxide dismutase (MnSOD) in relation to DOX sensitivity was analyzed after the modulation of MnSOD expression. The NF‐κB activity was much higher in DOX‐resistant SNU‐216 cells than in DOX‐sensitive SNU‐601 cells before and after DOX treatment. Overexpression of mIκBα 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‐κB 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‐κB activity. Our results showed that whether NF‐κB contributes to DOX sensitivity in gastric cancer cells is determined by the level of MnSOD expression. Thus, targeting both MnSOD and NF‐κB may be helpful for increasing the efficacy of DOX treatment of DOX‐resistant SNU gastric cancer cells. ( Cancer Sci 2008; 99: 1117–1124)