Nuclear Factor-κB induced by doxorubicin is deficient in phosphorylation and acetylation and represses nuclear factor-κB-dependent transcription in cancer cells

The primary goal of chemotherapy is to cause cancer cell death. However, a side effect of many commonly used chemotherapeutic drugs is the activation of nuclear factor-kappa B (NF-kappa B), a potent inducer of antiapoptotic genes, which may blunt the therapeutic efficacy of these compounds. We have assessed the effect of doxorubicin, an anthracycline in widespread clinical use, on NF-kappa B activation and expression of antiapoptotic genes in breast cancer cells. We show that doxorubicin treatment activates NF-kappa B signaling and produces NF-kappa B complexes that are competent for NF-kappa B binding in vitro. Surprisingly, these NF-kappa B complexes suppress, rather than activate, constitutive-and cytokine-induced NF-kappa B-dependent transcription. We show that doxorubicin treatment produces RelA, which is deficient in phosphorylation and acetylation and which blocks NF-kappa B signaling in a histone deacetylase-independent manner, and we show that NF-kappa B activated by doxorubicin does not remain stably bound to kappa B elements in vivo. Together these data show that NF-kappa B signaling induced by doxorubicin reduces expression of NF-kappa B-dependent genes in cancer cells.