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Valproic Acid Sensitizes TRAIL-Resistant Anaplastic Thyroid Carcinoma Cells to Apoptotic Cell Death.

Authors
Cha, HY | Lee, BS  | Kang, S | Shin, YS  | Chang, JW  | Sung, ES | Kim, YS | Choi, JW | Kim, JH  | Kim, CH
Citation
Annals of surgical oncology, 20 Suppl 3. : 716-724, 2013
Journal Title
Annals of surgical oncology
ISSN
1068-92651534-4681
Abstract
BACKGROUND: Anaplastic thyroid carcinoma (ATC) is an aggressive human tumor associated with a median survival of 2-6 months. TRAIL, as a ligand of death receptors, is known to induce apoptotic cell death in several cancer cells. However, TRAIL treatment alone is not effective against TRAIL-resistant cancer cells. This study was designed to investigate whether valproic acid (VPA) enhances apoptotic cell death of TRAIL-resistant ATC cells and to identify the mechanism of cell death of ATC cells by combination treatment with VPA and TRAIL.



METHODS: To evaluate the cytotoxic effect of TRAIL and/or VPA on ATC cells, we used the MTT assay. The effects of VPA and TRAIL on apoptosis were assessed using FACS analysis (Annexin-V/PI stain) and Western blotting.



RESULTS: The combination of VPA with TRAIL significantly induced apoptotic cell death compared with 8505C and ARO cells treated with TRAIL alone. The protein levels of cleaved caspase-8, -3, and PARP were increased in VPA and TRAIL co-treated ARO cells. The combination induced the activation of JNK and the phosphorylation of FADD and c-Jun but not p38. However, pretreatment with caspase inhibitors reduced the expression of cleaved caspase-8, -3, and PARP in co-treated ARO cells. SP600125 remarkably reduced the expression of cleaved caspase-8, -3, and PARP and the phosphorylation of FADD and c-Jun, as well as apoptotic cell death.



CONCLUSIONS: VPA sensitized TRAIL-resistant ATC cells to apoptotic cell death through involvement of the JNK pathway. Thus, the combination of VPA and TRAIL may be a promising therapy for ATC.
DOI
10.1245/s10434-013-3232-y
PMID
23982257
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Otolaryngology
Journal Papers > School of Medicine / Graduate School of Medicine > Pathology
Ajou Authors
김, 장희  |  김, 철호  |  신, 유섭  |  이, 복순  |  장, 재원
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