Cardiac glycosides initiate Apo2L/TRAIL-induced apoptosis in non-small cell lung cancer cells by up-regulation of death receptors 4 and 5
Cardiac glycosides initiate Apo2L/TRAIL-induced apoptosis in non-small cell lung cancer cells by up-regulation of death receptors 4 and 5
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DOI：
10.1158/0008-5472.can-05-3544
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发表时间：
2006-06-01
期刊：
影响因子：
11.2
通讯作者：
Schmid, RA
中科院分区：
文献类型：
--
作者：
Frese, S;Frese-Schaper, M;Schmid, RA
肿瘤坏死因子 (TNF) 相关凋亡诱导配体 (Apo2L/TRAIL) 属于 TNF 家族，已知可通过细胞膜受体转导死亡信号。由于已证明 Apo2L/TRAIL 可诱导肿瘤细胞凋亡，而对正常细胞没有或几乎没有毒性，因此这种细胞因子引起了癌症研究的特别关注。不幸的是，癌细胞通常对 Apo2L/TRAIL 诱导的细胞凋亡具有抵抗力。然而，这至少可以部分地通过与其他物质（例如化疗剂）的平行治疗来解决。在此，我们报道了多年来用于治疗心力衰竭的强心苷使肺癌细胞对 Apo2L/TRAIL 诱导的细胞凋亡敏感，但对正常人外周血单核细胞不敏感。强心苷介导的 Apo2L/TRAIL 致敏伴随着死亡受体 4 (DR4) 和 5 (DR5) 在 RNA 和蛋白质水平上的上调。小干扰RNA的使用表明，死亡受体的上调对于细胞凋亡的增强至关重要。与强心苷和 Apo2L/TRAIL 联合治疗后，单独阻断 DR4 和 DR5 的上调可显着减少细胞死亡。 DR4 和 DR5 的联合沉默消除了强心苷和 Apo2L/TRAIL 以累加方式诱导细胞凋亡的能力。据我们所知，这是首次证明糖苷上调 DR4 和 DR5，从而恢复肺癌细胞对 Apo2/TRAIL 诱导的细胞凋亡的抵抗力。我们的数据表明，Apo2L/TRAIL 和强心苷的组合可能是一种新的有趣的抗癌治疗策略。
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL) belongs to the TNF family known to transduce their death signals via cell membrane receptors. Because it has been shown that Apo2L/TRAIL induces apoptosis in tumor cells without or little toxicity to normal cells, this cytokine became of special interest for cancer research. Unfortunately, cancer cells are often resistant to Apo2L/TRAIL-induced apoptosis; however, this can be at least partially negotiated by parallel treatment with other substances, such as chemotherapeutic agents. Here, we report that cardiac glycosides, which have been used for the treatment of cardiac failure for many years, sensitize lung cancer cells but not normal human peripheral blood mononuclear cells to Apo2L/TRAIL-induced apoptosis. Sensitization to Apo2L/TRAIL mediated by cardiac glycosides was accompanied by up-regulation of death receptors 4 (DR4) and 5 (DR5) on both RNA and protein levels. The use of small interfering RNA revealed that up-regulation of death receptors is essential for the demonstrated augmentation of apoptosis. Blocking of up-regulation of DR4 and DR5 alone significantly reduced cell death after combined treatment with cardiac glycosides and Apo2L/TRAIL. Combined silencing of DR4 and DR5 abrogated the ability of cardiac glycosides and Apo2L/TRAIL to induce apoptosis in an additive manner. To our knowledge, this is the first demonstration that glycosides upregulate DR4 and DR5, thereby reverting the resistance of lung cancer cells to Apo2/TRAIL-induced apoptosis. Our data suggest that the combination of Apo2L/TRAIL and cardiac glycosides may be a new interesting anticancer treatment strategy.