Differential response of head and neck cancer cell lines to TRAIL or Smac mimetics is associated with the cellular levels and activity of caspase-8 and caspase-10
Background: Current treatments for head and neck cancer lead to considerable morbidity, and up to 50% of patients experience relapse, underscoring the urgent need for more targeted and effective therapies. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Smac mimetics (SMs) show promise as anticancer agents, though their specific effects on head and neck squamous cell carcinoma (HNSCC) have not been fully studied.
Methods: We tested the response of nine HNSCC cell lines to TRAIL and SMs, analyzing the mechanisms underlying cell type-specific responses through functional assays.
Results: The HNSCC cell lines displayed opposite response patterns: three cell lines were highly sensitive to Smac-164 (an SM) but resistant to TRAIL, while the other six were SM-164 TRAIL-sensitive but SM-resistant. Unique protein expression and activation profiles correlated with these responses. TRAIL sensitivity was linked to high levels of caspase-8 and Bid proteins, with TRAIL-sensitive cells undergoing apoptosis via the type II extrinsic pathway. In contrast, Smac mimetic-sensitive cells exhibited low levels of caspase-8 and Bid but high TNF-α expression, with SM-induced cell death associated with caspase-10 activation, suggesting caspase-10 compensates in the absence of caspase-8. Additionally, TNF-α co-treatment sensitized resistant cells to SM, highlighting the role of a TNF-α-driven feedback loop in SM sensitivity.
Conclusions: TRAIL and SMs effectively target HNSCC cell lines, positioning them as potential targeted treatments for head and neck cancer. Sensitivity to each agent is governed by specific molecular pathways, with TNF-α levels being a critical factor for SM response.