HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in breast carcinoma

• Published in: Oncogene Vol. 24; no. 29; pp. 4609 - 4623
• Main Authors: SINGH, Thiyam Ramsing, SHANKAR, Sharmila, SRIVASTAVA, Rakesh K
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 07.07.2005; Nature Publishing Group
• Subjects: Ageing, cell death; Apoptosis; Apoptosis Regulatory Proteins; Bcl-2 protein; Biological and medical sciences; Breast cancer; Breast carcinoma; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer therapies; Cell cycle; Cell physiology; Cell signaling; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cyclin-dependent kinases; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Genes; Gynecology. Andrology. Obstetrics; Histone deacetylase; Histone Deacetylase Inhibitors; Humans; Hydroxamic acid; Kinases; Ligands; Mammary gland diseases; Medical sciences; Membrane Glycoproteins - physiology; Mitochondria; Molecular and cellular biology; NF-κB protein; Pharmaceutical sciences; Pharmacy; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand; TRAIL protein; Transcription activation; Trichostatin A; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - physiology; Tumors; United States > US; Baltimore Maryland; Breast cancer; Malignant tumor; TRAIL/Apo-2L; Carcinogenesis; death receptors; Breast carcinoma; Mammary gland diseases; histone deacetylase inhibitor; Death; Inhibitor; Histone; Apoptosis; Biological receptor
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1208585

Histone deacetylase (HDAC) inhibitors induce differentiation and/or apoptosis in a variety of cell types by activating transcription of target genes. Activation of the death receptor (DR) pathway by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis preferentially in cancer cells. Here, we investigated the intracellular mechanisms by which HDAC inhibitors (suberoylanilide hydroxamic acid, m-carboxycinnamic acid bis-hydroxamide, MS-275 and trichostatin A) enhance the apoptosis-inducing potential of TRAIL in breast cancer cells in vitro. A synergism in apoptosis was observed in both TRAIL-sensitive and -resistant cells upon sequential treatments with HDAC inhibitors followed by TRAIL. HDAC inhibitors synergized with TRAIL by inducing DRs DR4/TRAIL-R1 and DR5/TRAIL-R2 through NFkappaB activation and some of the proapoptotic members of the Bcl-2 family, and engaging the mitochondrial pathway. The ability of HDAC inhibitors to sensitize TRAIL-resistant cells suggests that HDAC inhibitors may induce fundamental alterations in cell signaling pathways. Thus, the sequential treatments with HDAC inhibitors followed by TRAIL may be used as a new therapeutic approach for the treatment of human cancers.