Inactivation of NF-kappaB by proteasome inhibition contributes to increased apoptosis induced by histone deacetylase inhibitors in human breast cancer cells.
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-kappaB, we investigated whether the proteasome inhibitor MG-132 would inhibit NF-kappaB 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-kappaB-activity. This increase of NF-kappaB 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-kappaB pathway by BAY 11-7085 or IkappaB-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.
Laboratory of Experimental Oncology, Department of Medical Oncology, Hospital Clínic, Institut d'Investigacions Biomédiques August Pi I Sunyer, and Department of Cell Biology and Pathology, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
Josep
J
Domingo-Domènech
Raffaella
R
Pippa
Marian
M
Tápia
Pere
P
Gascón
Oriol
O
Bachs
Marta
M
Bosch
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D003114:Colony-Forming Units Assay; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors; D007976:Leupeptins / Q000494:pharmacology*; D008156:Luciferases / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D000077337:Vorinostat
C416282:BAY 11-7085; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D020672:I-kappa B Proteins; D007976:Leupeptins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009570:Nitriles; D013450:Sulfones; D000072000:NF-KappaB Inhibitor alpha; C012589:trichostatin A; D000077337:Vorinostat; D008156:Luciferases; D020169:Caspases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde