Synergistic induction of apoptosis in breast cancer cells by cotreatment with butyrate and TNF-alpha, TRAIL, or anti-Fas agonist antibody involves enhancement of death receptors' signaling and requires P21waf1

摘要: Abstract Inhibitors of histone deacetylase (HDAC) are considered as potential anticancer agents. We have previously demonstrated that an inhibitor HDAC, sodium butyrate (NaB), induces apoptosis breast cancer cells in a P53-independent and P21waf1-dependent manner. In this study, we showed tumor necrosis factor-alpha (TNF-alpha), TNF-related apoptosis-inducing ligand (TRAIL), anti-Fas agonist antibody potentiated NaB-induced growth inhibition through synergistic induction cell lines (MCF-7, T47-D, BT-20). MCF-7 cells, NaB increased the expression death receptors; alone or combination with TNF-alpha, TRAIL, levels Bid, tBid, cytosolic cytochrome c. Synergistic was strongly inhibited by dominant-negative Fas-associated domain (FADD) inhibitors caspases-8 -9, indicating potentiation involved key elements receptors' signaling pathways. Moreover, cotreatment ligands receptors up-regulated P21waf1 proliferating nuclear antigen (PCNA) associated P21waf1. Transient transfections p21waf1 antisense deficient for its interaction PCNA abolished apoptosis. This suggested cotreatments required PCNA. Since tumors contain rarely p21 mutations, our results may open interesting prospects fight against cancer.