Department of Cogno-Mechatronics Engineering, BK21 Nanofusion Technology Team, Pusan National University, Busan 609-735, Korea.
Int J Oncol. 2010 Apr;36(4):1023-30.
The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been used to treat a variety of cancer cells. However, since some gastric cancer cells are resistant to TRAIL, we explored whether reovirus induces cytolysis in TRAIL-resistant gastric cancer cells. We found that TRAIL-resistant SNU-216 gastric cancer cells were susceptible to apoptosis by reovirus infection. Furthermore, co-treatment with reovirus and TRAIL accelerated apoptosis of SNU-216 cells by down-regulation of Akt activation as assessed by a very low activation of Akt in TRAIL-sensitive SNU-668 gastric cancer cells. Inhibition of Akt signaling with wortmannin or suppression of Akt expression with sh-Akt lentivirus promoted reovirus-mediated apoptosis of SNU-216 gastric cancer cells. Reovirus infection also down-regulates the activation of signaling molecules such as Ras and ERK involved in cell proliferation and survival but not the activation of p38 MAPK involved in cellular stress. In addition, the co-treatment with reovirus and TRAIL resulted in cleavage of caspase-8, caspase-9 and Bid, leading to a decrease in the mitochondrial membrane potential, indicating that reovirus may utilize the mitochondrial intrinsic apoptotic pathway in TRAIL-resistant SNU-216 gastric cancer cells. Accordingly, we first demonstrate that reovirus infection down-regulates Akt activation, leading to apoptosis of TRAIL-resistant gastric cancer cells.
肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）已被用于治疗多种癌细胞。然而，由于一些胃癌细胞对 TRAIL 具有抗性，我们探讨了呼肠孤病毒是否会诱导 TRAIL 抗性胃癌细胞发生细胞溶解。我们发现呼肠孤病毒感染可使 TRAIL 抗性 SNU-216 胃癌细胞发生凋亡。此外，通过 TRAIL 敏感的 SNU-668 胃癌细胞中 Akt 的极低激活，我们发现呼肠孤病毒与 TRAIL 联合处理可加速 SNU-216 细胞的凋亡，下调 Akt 的激活。用渥曼青霉素抑制 Akt 信号通路或用 sh-Akt 慢病毒抑制 Akt 表达，可促进 SNU-216 胃癌细胞中呼肠孤病毒介导的细胞凋亡。呼肠孤病毒感染还可下调与细胞增殖和存活相关的信号分子如 Ras 和 ERK 的激活，但不影响与细胞应激相关的 p38 MAPK 的激活。此外，呼肠孤病毒与 TRAIL 的联合处理可导致 caspase-8、caspase-9 和 Bid 的切割，导致线粒体膜电位降低，表明呼肠孤病毒可能在 TRAIL 抗性 SNU-216 胃癌细胞中利用线粒体内在凋亡途径。因此，我们首次证明呼肠孤病毒感染可下调 Akt 的激活，导致 TRAIL 抗性胃癌细胞的凋亡。
