Nuclear Factor-κB Induced by Doxorubicin Is Deficient in Phosphorylation and Acetylation and Represses Nuclear Factor-κB–Dependent Transcription in Cancer Cells

Abstract

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-KB (NF-KB), 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-KB activation and expression of antiapoptotic genes in breast cancer cells. We show that doxorubicin treatment activates NF-KB signaling and produces NF-KB complexes that are competent for NF-KB binding in vitro. Surprisingly, these NF-KB complexes suppress, rather than activate, constitutiveand cytokine-induced NF-KB-dependent transcription. We show that doxorubicin treatment produces RelA, which is deficient in phosphorylation and acetylation and which blocks NF-KB signaling in a histone deacetylase-independent manner, and we show that NF-KB activated by doxorubicin does not remain stably bound to KB elements in vivo. Together these data show that NF-KB signaling induced by doxorubicin reduces expression of NF-KB-dependent genes in cancer cells.

Differential effects of NF-κB on apoptosis induced by DNA-damaging agents: the type of DNA damage determines the final outcome

“…Accordingly, NF-kB induced by doxorubicin was found to bind endogenous loci and to assemble a histone deacetylase-dependent transcriptional repressor complex (Campbell et al, 2004). Alternatively, repression may result from unstable binding of NF-kB to endogenous loci owing to deficiency of p65 in phosphorylation and acetylation (Ho et al, 2005).…”

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

“…Interestingly, it was found that daunorubicin induced the association of RelA with the histone deacetylases 1, 2 and 3, consistent with the role for NF-kB in repressing gene expression downstream of responses to that chemotherapy. A similar report indicated that doxorubicin-induced NF-kB is deficient in transcriptional activity, which is associated with reduced phosphorylation and acetylation of RelA (Ho et al, 2005). In addition, NF-kB activation by doxorubicin in four colorectal cancer cells is required for the anticancer efficacy of the drug (Ashikawa et al, 2004).…”

p53-induced protein with a death domain (PIDD) isoforms differentially activate nuclear factor-kappaB and caspase-2 in response to genotoxic stress

“…Indeed, doxorubicin has been shown to repress some NF-kB-driven genes by assembling a histone deacetylase-dependent transcriptional repressor complex (Campbell et al, 2004(Campbell et al, , 2006. It has also been observed that doxorubicin leads to a deficiency in phosphorylation and acetylation of p65, resulting in unstable binding of NF-kB to endogenous loci (Ho et al, 2005). The loss of p53 accentuates the decrease in isoform 3 mRNA levels, indicating that both p53 and (at least) another transcription factor, maybe NF-kB, control PIDD expression.…”