Department of Dermatology, Sapporo Medical University School of Medicine , Sapporo, Hokkaido, Japan.
J Interferon Cytokine Res. 2010 May;30(5):349-57. doi: 10.1089/jir.2009.0015.
Interferon (IFN) is believed to be one of the most effective anti-melanoma agents. Specifically, IFN-beta has the ability to induce apoptosis of melanoma cells. Induction of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has also been suggested to have a critical role in IFN-beta-induced apoptosis. To characterize the signaling pathway involved in IFN-beta-induced apoptosis, we analyzed the biological effects of IFN-beta on the cell death and caspase activation of melanoma cells. IFN-sensitive cell lines, MM418, SK-mel-23, and SK-mel-118, showed increased apoptotic populations correlated with the activation of caspase-2 and caspase-3 by IFN-beta. IFN-beta-induced apoptosis was significantly suppressed by inhibitors for caspase-2 or caspase-3, but not by inhibitors for caspase-8 or caspase-9 in these cell lines. TRAIL expression was observed in IFN-beta-treated cells of SK-mel-23 and SK-mel-118, but not in those cells of MM418, which showed massive IFN-beta-induced apoptosis and resistance to exogenous TRAIL-mediated apoptosis. G361 was resistant to IFN-beta-induced apoptosis but sensitive to exogenous TRAIL-mediated apoptosis. Furthermore, IFN-beta pretreatment significantly increased the sensitivity against exogenous TRAIL-mediated apoptosis and activation of caspase-2 in G361. These results suggested that caspase-2 activation is commonly associated with induction of IFN-beta-induced apoptosis in IFN-beta-sensitive melanoma cells.
干扰素（IFN）被认为是最有效的抗黑色素瘤药物之一。具体来说，IFN-β 能够诱导黑色素瘤细胞凋亡。诱导肿瘤坏死因子相关凋亡诱导配体（TRAIL）也被认为在 IFN-β 诱导的凋亡中起关键作用。为了描述 IFN-β 诱导的凋亡所涉及的信号通路，我们分析了 IFN-β 对黑色素瘤细胞死亡和半胱天冬酶激活的生物学效应。IFN 敏感细胞系 MM418、SK-mel-23 和 SK-mel-118 显示出与 IFN-β 激活 caspase-2 和 caspase-3 相关的凋亡细胞群体增加。在这些细胞系中，IFN-β 诱导的凋亡被 caspase-2 或 caspase-3 的抑制剂显著抑制，但 caspase-8 或 caspase-9 的抑制剂则没有抑制作用。在 SK-mel-23 和 SK-mel-118 的 IFN-β 处理细胞中观察到 TRAIL 表达，但在 MM418 细胞中则没有，后者表现出大量 IFN-β 诱导的凋亡和对 TRAIL 介导的凋亡的抗性。G361 对 IFN-β 诱导的凋亡有抗性，但对 TRAIL 介导的凋亡有敏感性。此外，IFN-β 预处理显著增加了 G361 对 TRAIL 介导的凋亡和 caspase-2 激活的敏感性。这些结果表明，caspase-2 的激活与 IFN-β 敏感的黑色素瘤细胞中 IFN-β 诱导的凋亡的诱导有关。
