Abstract | BACKGROUND: METHODS: c-FLIP expression was assessed by real-time PCR and compared according to clinical parameters in patients with PTCLs. The relation of c-FLIP to tumor cell apoptosis mediated by histone deacetylases inhibitors (HDACIs) and the possible mechanism were examined in T- lymphoma cell lines and in a murine xenograft model. RESULTS: c-FLIP was overexpressed and associated with decreased tumor TRAIL/DR5 expression, elevated serum lactate dehydrogenase level and high-risk International Prognostic Index of the patients. In vitro, molecular silencing of c-FLIP by specific small-interfering RNA increased TRAIL/DR5 expression, enhanced T- lymphoma cell apoptosis and sensitized cells to chemotherapeutic agents. However, HDACIs valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) could downregulate c-FLIP expression and triggered extrinsic apoptosis of T- lymphoma cells, through inhibiting NF-κB signaling and interrupting P50 interaction with c-FLIP promoter. As Class I HDACIs, both VPA and SAHA inhibited HDAC1, resulting in P50 inactivation and c-FLIP downregulation. In vivo, oral VPA treatment significantly retarded tumor growth and induced in situ apoptosis, consistent with inhibition of HDAC1/P50/c-FLIP axis and increase of TRAIL/DR5 expression. CONCLUSIONS: c-FLIP overexpression in PTCLs protected tumor cells from extrinsic apoptosis and contributed to tumor progression. Although linking to chemoresistance, c-FLIP indicated tumor cell sensitivity to HDACIs, providing a potential biomarker of targeting apoptosis in treating PTCLs.
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Authors | Zhong Zheng, Shu Cheng, Wen Wu, Li Wang, Yan Zhao, Yang Shen, Anne Janin, Wei-Li Zhao |
Journal | Journal of hematology & oncology
(J Hematol Oncol)
Vol. 7
Pg. 88
(Dec 05 2014)
ISSN: 1756-8722 [Electronic] England |
PMID | 25477070
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- CASP8 and FADD-Like Apoptosis Regulating Protein
- Histone Deacetylase Inhibitors
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Topics |
- Apoptosis
(drug effects, physiology)
- CASP8 and FADD-Like Apoptosis Regulating Protein
(biosynthesis)
- Cell Line, Tumor
- Disease Progression
- HEK293 Cells
- Histone Deacetylase Inhibitors
(pharmacology)
- Humans
- Jurkat Cells
- Lymphoma, T-Cell, Peripheral
(drug therapy, metabolism, pathology)
- Molecular Targeted Therapy
- Signal Transduction
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