TNF-related apoptosis-inducing ligand (TRAIL) and an agonistic antibody against the death-inducing TRAIL receptor 5, DR5, are thought to selectively induce tumor cell death and therefore, have gained attention as potential therapeutics currently under investigation in several clinical trials. However, some tumor cells are resistant to TRAIL/DR5–induced cell death, even though they express DR5. Previously, we reported that DR5 is transported into the nucleus by importin β1, and knockdown of importin β1 upregulates cell surface expression of DR5 resulting in increased TRAIL sensitivity in vitro. Here, we examined the impact of importin β1 knockdown on agonistic anti-human DR5 (hDR5) antibody therapy. Drug-inducible importin β1 knockdown sensitizes HeLa cells to TRAIL-induced cell death in vitro, and exerts an antitumor effect when combined with agonistic anti-hDR5 antibody administration in vivo. Therapeutic importin β1 knockdown, administered via the atelocollagen delivery system, as well as treatment with the importin β inhibitor, importazole, induced regression and/or eradication of two human TRAIL-resistant tumor cells when combined with agonistic anti-hDR5 antibody treatment. Thus, these findings suggest that the inhibition of importin β1 would be useful to improve the therapeutic effects of agonistic anti-hDR5 antibody against TRAIL-resistant cancers.

中文翻译：

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抑制输入蛋白 β1 增强激动性抗死亡受体 5 抗体在 TNF 相关凋亡诱导配体抗性肿瘤细胞中的抗癌作用

TNF 相关的凋亡诱导配体 (TRAIL) 和针对死亡诱导性 TRAIL 受体 5 DR5 的激动性抗体被认为可选择性诱导肿瘤细胞死亡，因此作为目前正在几项临床试验中研究的潜在疗法已受到关注。然而，一些肿瘤细胞对 TRAIL/DR5 诱导的细胞死亡具有抗性，即使它们表达 DR5。以前，我们报道了 DR5 通过输入蛋白 β1 转运到细胞核中，输入蛋白 β1 的敲低上调了 DR5 的细胞表面表达，导致体外 TRAIL 敏感性增加。在这里，我们检查了输入蛋白 β1 敲低对激动性抗人 DR5 (hDR5) 抗体治疗的影响。药物诱导的输入蛋白 β1 敲低使 HeLa 细胞在体外对 TRAIL 诱导的细胞死亡敏感，并在体内与激动性抗 hDR5 抗体联合给药时发挥抗肿瘤作用。治疗性输入蛋白 β1 敲低，通过去端肽胶原递送系统给药，以及使用输入蛋白 β 抑制剂输入唑进行治疗，当与激动性抗 hDR5 抗体治疗相结合时，诱导消退和/或根除两种人类 TRAIL 抗性肿瘤细胞。因此，这些发现表明抑制输入蛋白 β1 将有助于改善激动性抗 hDR5 抗体对 TRAIL 抗性癌症的治疗效果。当与激动性抗 hDR5 抗体治疗结合时，诱导消退和/或根除两种人类 TRAIL 抗性肿瘤细胞。因此，这些发现表明抑制输入蛋白 β1 将有助于改善激动性抗 hDR5 抗体对 TRAIL 抗性癌症的治疗效果。当与激动性抗 hDR5 抗体治疗结合时，诱导消退和/或根除两种人类 TRAIL 抗性肿瘤细胞。因此，这些发现表明抑制输入蛋白 β1 将有助于改善激动性抗 hDR5 抗体对 TRAIL 抗性癌症的治疗效果。