α-Tocopheryl succinate-induced apoptosis in human gastric cancer cells is modulated by ERK1/2 and c-Jun N-terminal kinase in a biphasic manner

Gastric neoplastic disease is one of the most frequent causes of cancer-associated deaths with poor prognosis. Here we studied the effect of the redox-silent analogue α-tocopheryl succinate (α-TOS), a strong apoptogen and anti-cancer agent, on the gastric cancer cell line SGC-7901. α-TOS inhibited proliferation of the cells and induced their apoptosis in a concentration- and time-dependent manner, while succinate or α-tocopherol showed no effect. The effect of α-TOS was modulated by components of the MAPK signaling network, including ERK1/2 and c-Jun N-terminal kinase (JNK), but not p38. Activation of ERK1/2 occurred early and increased until 12 h, coinciding with an in crease in apoptosis in the cells, after which it dropped abruptly, while activation of JNK rose steadily, reaching a plateau at 12 h of α-TOS treatment. The effects of ERK1/2 and JNK on the apoptosis outcome are transmitted via c-Jun, since transfection of the cells with c-Jun antisense oligodeoxynucleotide inhibited α-TOS-induced apoptosis. We conclude that ERK1/2 and JNK positively regulate apoptosis induced in gastric cancer cells by α-TOS.