Tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL) is an inducer of
cancer cell death that holds promise in
cancer therapy.
Cancer cells are more susceptible than normal cells to the cell-death-inducing effects of TRAIL. However, a variety of
cancer cells are resistant to TRAIL through complex mechanisms. Here, we investigate the effects of inhibition of
eukaryotic initiation factor 2 subunit α (eIF2α) dephosphorylation on TRAIL-induced apoptosis in
hepatoma cells. Treatment of
hepatoma cells with
salubrinal, an inhibitor of eIF2α dephosphorylation, enhances TRAIL-induced eIF2α phosphorylation,
CCAAT/enhancer-binding protein homologous
protein (CHOP) expression and
caspase activation.
Salubrinal enhances TRAIL-induced apoptosis, which could be abrogated by
caspase inhibitor. Overexpression of phosphomimetic eIF2α (S51D) enhances TRAIL-induced CHOP expression,
caspase 7 and PARP cleavage and apoptosis. By contrast, overexpression of phosphodeficient eIF2α (S51A) abrogates the stimulation of TRAIL-induced apoptosis by
salubrinal. Moreover, knockdown of growth arrest and DNA damage-inducible
protein 34 (GADD34), which recruits
protein phosphatase 1 to dephosphorylate eIF2α, enhances TRAIL-induced eIF2α phosphorylation, CHOP expression,
caspase activation and apoptosis. Furthermore, the sensitization of
hepatoma cells to TRAIL by
salubrinal is dependent on CHOP. Knockdown of CHOP abrogates the stimulation of TRAIL-induced
caspase activation and apoptosis by
salubrinal. Combination of
salubrinal and TRAIL leads to increased expression of Bim, a CHOP-regulated proapoptotic
protein. Bim knockdown blunts the stimulatory effect of
salubrinal on TRAIL-induced apoptosis. Collectively, these findings suggest that inhibition of eIF2α dephosphorylation may lead to synthetic lethality in TRAIL-treated
hepatoma cells.