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

Abstract

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. © 2008 Japanese Cancer Association.