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

• Published in: Breast cancer research and treatment 2008-11, Vol.112 (1), p.53-62
• Main Authors: Domingo-Domènech, Josep, Pippa, Raffaella, Tápia, Marian, Gascón, Pere, Bachs, Oriol, Bosch, Marta
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Gynecology. Andrology. Obstetrics; Mammary gland diseases; Medical sciences; Medicine; Medicine & Public Health; Oncology; Preclinical Study; Tumors
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-007-9837-8

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.