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Inactivation of NF-κB by proteasome inhibition contributes to increased apoptosis induced by histone deacetylase inhibitors in human breast cancer cells

Abstract

Histone deacetylase inhibitors (HDACi) are a new class of anticancer agents that cause growth arrest, differentiation and/or apoptosis in many tumor cells. As acetylation regulates the activity of the anti-apoptotic transcription factor NF-κB, we investigated whether the proteasome inhibitor MG-132 would inhibit NF-κB activation and as a consequence potentiate HDACi-dependent apoptosis in breast cancer cells. We observed that the HDACi suberoylanilide hydroxamic acid (SAHA) or trichostatin A (TSA) induced cell death but also enhanced NF-κB-activity. This increase of NF-κB activity was strongly reduced by the addition of MG-132. Moreover, MG-132 potentiates the HDACi-induced cell death that was associated with caspase-3 activation, and PARP cleavage. Induction of the stress related kinases JNK and p38 and the up-regulation of p21 and p27 were also observed after co-treatment of cells with HDACi and MG-132. Disruption of the NF-κB pathway by BAY 11-7085 or IκB-SR mimicked the action of MG-132 in promoting HDACi-induced cell death. Thus, the combined treatment with HDACi and proteasome inhibitors potentiates apoptosis in breast cancer cells representing a novel strategy for breast cancer therapy.

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Acknowledgements

This work was supported by Grant SAF 2003–08329 from the Ministerio de Educación y Ciencia of Spain.

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Correspondence to Marta Bosch.

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Domingo-Domènech, J., Pippa, R., Tápia, M. et al. Inactivation of NF-κB by proteasome inhibition contributes to increased apoptosis induced by histone deacetylase inhibitors in human breast cancer cells. Breast Cancer Res Treat 112, 53–62 (2008). https://doi.org/10.1007/s10549-007-9837-8

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  • DOI: https://doi.org/10.1007/s10549-007-9837-8

Keywords

  • HDAC inhibitor
  • SAHA
  • Proteasome inhibition
  • NF-κB
  • Breast cancer
  • Apoptosis