Valproic acid sensitizes TRAIL-resistant anaplastic thyroid carcinoma cells to apoptotic cell death
Hyun-Young Cha1, Bok-Soon Lee, Sam Kang
1Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Korea.
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.
Insights
Valproic acid (VPA) sensitizes anaplastic thyroid carcinoma (ATC) cells to TRAIL-induced apoptosis. This combination therapy, involving VPA and TRAIL, shows promise for treating aggressive ATC by activating the JNK pathway.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Anaplastic thyroid carcinoma (ATC) is an aggressive cancer with poor prognosis.
- TRAIL induces apoptosis but is ineffective in TRAIL-resistant cancer cells.
- Valproic acid (VPA) is investigated for its potential to enhance TRAIL efficacy.
Purpose of the Study:
- To determine if VPA enhances TRAIL-induced apoptosis in TRAIL-resistant ATC cells.
- To elucidate the mechanism of cell death induced by the combination of VPA and TRAIL.
Main Methods:
- Cytotoxicity assessed using MTT assay.
- Apoptosis evaluated by FACS analysis (Annexin-V/PI staining).
- Protein expression and activation analyzed via Western blotting.
Main Results:
- VPA and TRAIL combination significantly increased apoptosis in ATC cells compared to TRAIL alone.
- Co-treatment elevated levels of cleaved caspase-8, -3, and PARP.
- Activation of JNK, FADD, and c-Jun was observed, indicating pathway involvement.
Conclusions:
- VPA sensitizes TRAIL-resistant ATC cells to apoptosis via the JNK pathway.
- The combination of VPA and TRAIL represents a potential therapeutic strategy for ATC.
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