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

Abstract

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. 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. 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. 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.