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

Centre for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada

Requests for reprints: Philip A. Barker, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec, Canada H3A 2B4. Phone: 514-398-3064; Fax: 514-398-5214; E-mail: phil.barker{at}mcgill.ca.

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

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