1. LBH589, a deacetylase inhibitor, induces apoptosis in adult T-cell leukemia/lymphoma cells via activation of a novel RAIDD-caspase-2 pathway.
- Author
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Hasegawa H, Yamada Y, Tsukasaki K, Mori N, Tsuruda K, Sasaki D, Usui T, Osaka A, Atogami S, Ishikawa C, Machijima Y, Sawada S, Hayashi T, Miyazaki Y, and Kamihira S
- Subjects
- Adult, Animals, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Blotting, Western, CRADD Signaling Adaptor Protein antagonists & inhibitors, CRADD Signaling Adaptor Protein genetics, Caspase 2 genetics, Caspase Inhibitors, Cell Proliferation drug effects, Female, Gene Expression Profiling, Histone Deacetylases metabolism, Humans, Immunoenzyme Techniques, Immunoprecipitation, Indoles, Leukemia-Lymphoma, Adult T-Cell genetics, Luciferases metabolism, Mice, Mice, SCID, Oligonucleotide Array Sequence Analysis, Panobinostat, RNA, Messenger genetics, RNA, Small Interfering genetics, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured, Apoptosis drug effects, CRADD Signaling Adaptor Protein metabolism, Caspase 2 metabolism, Histone Deacetylases chemistry, Hydroxamic Acids pharmacology, Leukemia-Lymphoma, Adult T-Cell metabolism, Leukemia-Lymphoma, Adult T-Cell pathology
- Abstract
Adult T-cell leukemia/lymphoma (ATLL), an aggressive neoplasm etiologically associated with human T-lymphotropic virus type-1 (HTLV-1), is resistant to treatment. In this study, we examined the effects of a new inhibitor of deacetylase enzymes, LBH589, on ATLL cells. LBH589 effectively induced apoptosis in ATLL-related cell lines and primary ATLL cells and reduced the size of tumors inoculated in SCID mice. Analyses, including with a DNA microarray, revealed that neither death receptors nor p53 pathways contributed to the apoptosis. Instead, LBH589 activated an intrinsic pathway through the activation of caspase-2. Furthermore, small interfering RNA experiments targeting caspase-2, caspase-9, RAIDD, p53-induced protein with a death domain (PIDD) and RIPK1 (RIP) indicated that activation of RAIDD is crucial and an event initiating this pathway. In addition, LBH589 caused a marked decrease in levels of factors involved in ATLL cell proliferation and invasion such as CCR4, IL-2R and HTLV-1 HBZ-SI, a spliced form of the HTLV-1 basic zipper factor HBZ. In conclusion, we showed that LBH589 is a strong inducer of apoptosis in ATLL cells and uncovered a novel apoptotic pathway initiated by activation of RAIDD.
- Published
- 2011
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