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 P21(waf1).
Inhibitors of histone deacetylase (HDAC) are considered as potential anticancer agents. We have previously demonstrated that an inhibitor of HDAC, sodium butyrate (NaB), induces apoptosis of breast cancer cells in a P53-independent and P21(waf1)-dependent manner. In this study, we showed that tumor necrosis factor-alpha (TNF-alpha), TNF-related apoptosis-inducing ligand (TRAIL), and anti-Fas agonist antibody potentiated NaB-induced growth inhibition through synergistic induction of apoptosis in breast cancer cell lines (MCF-7, T47-D, and BT-20). In MCF-7 cells, NaB increased the expression of death receptors; NaB alone or in combination with TNF-alpha, TRAIL, and anti-Fas agonist antibody increased the levels of Bid, tBid, and that of cytosolic cytochrome c. Synergistic induction of apoptosis was strongly inhibited by dominant-negative Fas-associated death domain (FADD) and inhibitors of caspases-8 and -9, indicating that potentiation of apoptosis involved key elements of death receptors' signaling pathways. Moreover, cotreatment of NaB and ligands of death receptors up-regulated the levels of P21(waf1) and that of proliferating cell nuclear antigen (PCNA) associated with P21(waf1). Transient transfections of p21(waf1) antisense or p21(waf1) deficient for its interaction with PCNA abolished synergistic induction of apoptosis. This suggested that potentiation of apoptosis by cotreatments required P21(waf1) and its interaction with PCNA. Since breast tumors contain rarely p21 mutations, our results may open interesting prospects in the fight against breast cancer.
Chopin
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V
Laboratoire de Biologie du Développement, UPRES-EA 1033, IFR-118, Université des Sciences et Technologies de Lille, Bâtiment SN3, 59655 Villeneuve d'Ascq Cedex, France.
Slomianny
C
C
Hondermarck
H
H
Le Bourhis
X
X
D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002087:Butyrates / Q000494:pharmacology / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D045304:Cytochromes c / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D053200:Fas-Associated Death Domain Protein; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology / Q000627:therapeutic use; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D019014:fas Receptor / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002087:Butyrates; C493956:CDKN1A protein, human; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D056572:Histone Deacetylase Inhibitors; D008562:Membrane Glycoproteins; D018809:Proliferating Cell Nuclear Antigen; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D045304:Cytochromes c; D020169:Caspases; D006655:Histone Deacetylases