Abstract
Although TRAIL can directly induce cell death in some cancer cells, it appears that TRAIL resistance exists in many cancers. This study focuses on anti-cancer drugs for TRAIL-resistant head and neck cancer (HNC) to provide further progress toward effective cancer therapy. Results indicate in TRAIL-resistant HNC cells, that combined TRAIL and VPA treatment greatly reduced cell viability and therefore induced cell death, relative to treatment with TRAIL or VPA alone. A caspase-dependent signaling pathway was demonstrated, and combined treatment with TRAIL and VPA also significantly decreased the expression of HDAC4. When we pretreated cells with z-VAD followed by combined treatment with TRAIL and VPA, cell death was blocked with no reduction in expression of HDAC4. To confirm that cell death involved HDAC4 in HNC cells, we knocked down expression of HDAC4 with siRNA, followed by treatment with TRAIL and VPA. Results showed that loss of HDAC4 sensitized the TRAIL-resistant HNC cells to apoptotic cell death. Finally, we showed elevated expression of HDAC4 in HNC tissues compared to normal tissues obtained from the same patients. In conclusion, we suggest that combined VPA and TRAIL treatment may be a promising therapy for HNC via HDAC4 degradation.
Highlights
TRAIL (tumor necrosis-factor (TNF)-related apoptosis-inducing ligand) is a member of the TNF family, and it usually induces apoptotic cell death in several different kinds of cancer cells without having an appreciable effect in normal cells[5]
We examined valproic acid (VPA) to determine the sensitivity of head and neck cancer (HNC) cells to TRAIL, which could result in apoptotic cell death, and in addition we identified the precise cell death mechanism
We wanted to apply it to this study and examine the head and neck cancer cells lines that are resistant to TRAIL
Summary
TRAIL (tumor necrosis-factor (TNF)-related apoptosis-inducing ligand) is a member of the TNF family, and it usually induces apoptotic cell death in several different kinds of cancer cells without having an appreciable effect in normal cells[5]. Once TRAIL binds to its receptor, oligomerization recruits downstream molecules, such as FAS-associated death domain (FADD), and is able to form the procaspase-8 activating death-inducing signaling complex (DISC)[7]. It has been implicated in triggering cell death physiological responses[7]. Our findings provide insights into the potential for combined treatment with TRAIL and VPA, which together induce apoptotic cell death via degradation of HDAC4. Our data suggest this approach has great potential as an anti-cancer strategy for head and neck cancers
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