Interferon-α sensitizes human gastric cancer cells to TRAIL-induced apoptosis via activation of the c-Cbl-dependent MAPK/ERK pathway

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family that induces apoptosis in cancer cells. However, gastric cancer cells are insensitive to TRAIL. In the present study, we show that pretreatment with IFN alpha enhanced TRAIL-induced apoptosis of gastric cancer cells. IFN alpha upregulated death receptor (DR) expression and downregulated survivin expression. Furthermore, extracellular-regulated protein kinase (ERK) activation was induced by IFN alpha, and a combination of IFN alpha and TRAIL led to further activation of ERK. Inhibition of the MAP K/ERK signaling pathway partially reversed apoptosis, as well as the expression patterns of DR4, DR5 and survivin, whereas inhibition of c-Jun NH2-terminal kinase (JNK) activation slightly attenuated the enhancement of TRAIL-induced apoptosis by IFN alpha. Moreover, the expression of the c-Casitas B-lineage lymphoma (c-Cbl) was downregulated by IFN alpha. Transfection of c-Cbl suppressed IFN alpha-induced ERK activation and DR upregulation, as well as the synergistic apoptosis-inducing effect of IFNa and TRAIL. In contrast, knockdown of c-Cbl enhanced the effect. These results indicate that IFN alpha enhances TRAIL-induced apoptosis in gastric cancer cells at least partially via downregulation of c-Cbl, and subsequent activation of the MAP K/ERK pathway.