Adriamycin-induced NF-κB activation and cytotoxicity: reevaluation of the role of NF-kB blockage in chemosensitization

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NF-κB is generally believed to be a cell survival signal that blunts the anticancer activities of cancer therapeutics. Adriamycin, a first-line anticancer drug used for lung cancer, induces NF-κB activation in lung cancer cells. Recently, controversial roles of NF-κB in regulating gene expression (activator or repressor) as well as in cancer cell’s sensitivity to adriamycin (pro-, anti-apoptotic or has no effect) have been suggested. It is important to clarify these issues in order to sensitize cancer cells to therapeutics. In this study, we found that adriamycin activated a NF-κB responsive luciferase reporter and induced expression of anti-apoptotic genes such as Bcl-XL and MnSOD in A549 and H460 lung cancer cells. Blockage of the NF-κB pathway by the IκBα super-suppressor (IκBαAA), or siRNA against RelA or NEMO effectively blocked the induction of the reporter and gene expression by adriamycin. These results suggest that adriamycin-induced NF-κB in lung cancer cells is transcriptionally active. Although the death receptor 5 (DR5) was reported to be a NF-κB target, blockage of NF-κB had marginal effect on adriamycin-induced DR5 expression, suggesting that adriamycin-induced expression of this apoptotic receptor does not require NF-κB. Additionally, blockage of NF-κB by targeting the key mediators of this pathway with siRNA against RelA or NEMO sensitized adriamycin-induced cytotoxicity, suggesting blocking the NF-κB pathway could sensitize lung cancer cells to adriamycin. Intriguingly, expression of IκBαAA did not affect adriamycin-induced cell death. Together with the reported non-NF-κB related effects of IκBαAA such as interfering p53, these results imply that overexpression of IκBαAA may not be an appropriate approach for sensitization of lung cancer to adriamycin. In sum, our results suggest that adriamycin-induced NF-κB is a transcriptional activator that protects lung cancer cells against the cytotoxicity triggered by this drug, and careful evaluation of NF-κB blocking approaches is necessary for sensitization of lung cancer cells to adriamycin.