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.
Original language | English (US) |
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Pages (from-to) | 53-62 |
Number of pages | 10 |
Journal | Breast Cancer Research and Treatment |
Volume | 112 |
Issue number | 1 |
DOIs | |
State | Published - Nov 2008 |
Keywords
- Apoptosis
- Breast cancer
- HDAC inhibitor
- NF-κB
- Proteasome inhibition
- SAHA
ASJC Scopus subject areas
- Oncology
- Cancer Research