Department of Gastroenterology and Hematology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
Cell Cycle. 2010 Jan 1;9(1):131-9. doi: 10.4161/cc.9.1.10250. Epub 2010 Jan 5.
Type I interferons (IFNs) are a family of cytokines that exhibit various biological activities. Besides their roles in immune response, IFNs have been known to modulate cell proliferation and to induce apoptosis. Thus, IFNs are used as an antitumor agent against certain types of cancer, but it is unclear why many other cancers are not influenced by IFNs. Here, we found that IFN-alpha2b, a subfamily of IFN-alpha, enhanced proliferation of HeLa cells, a cell line derived from human cervical cancer. IFN-alpha2b was rather inhibitory on the growth of other types of cervical cancer cells including those positive for HPV. Among the proliferation- and the apoptosis-related genes, p21(cip1/waf1) (p21) was upregulated by IFN-alpha2b, whereas p53, p27 or BCL-2 associated X protein (BAX) was not affected. IFN-alpha2b did not alter promoter activities of p21 but did prolong the decay of p21 mRNA. In contrast, the level of p21 protein was lowered by IFN-alpha2b, and half-life analysis of p21 protein revealed that IFN-alpha2b enhances p21 protein instability in HeLa cells. Pretreatment of the cells with MG132, a proteasome inhibitor, abolished the IFN-alpha2b-mediated p21 degradation, suggesting that IFN-alpha2b accelerated the ubiquitin-proteasome dependent degradation of p21. Consistent with these results, IFN-alpha2b increased S-phase cell cycle distribution in HeLa cells. In addition, IFN-alpha2b liberated the cells from G(1)-phase arrest by 5-fluorouracil (5-FU) and from G(2)-phase arrest by paclitaxel. These results provide a novel role of Type I IFNs in cell cycle regulation and may define an importance of individualized IFN-based therapy against specific types of cancer.
I 型干扰素（IFN）是一类具有多种生物学活性的细胞因子。除了在免疫反应中的作用外，IFN 还被认为可以调节细胞增殖并诱导细胞凋亡。因此，IFN 被用作针对某些类型癌症的抗肿瘤药物，但尚不清楚为什么许多其他癌症不受 IFN 的影响。在这里，我们发现 IFN-α2b（IFN-α 的一个亚家族）增强了来自人宫颈癌的 HeLa 细胞的增殖。IFN-α2b 对其他类型的宫颈癌细胞的生长具有抑制作用，包括 HPV 阳性的细胞。在与增殖和凋亡相关的基因中，p21(cip1/waf1)（p21）被 IFN-α2b 上调，而 p53、p27 或 BCL-2 相关 X 蛋白（BAX）不受影响。IFN-α2b 不改变 p21 的启动子活性，但可延长 p21 mRNA 的衰减。相反，IFN-α2b 降低了 p21 蛋白的水平，p21 蛋白半衰期分析表明 IFN-α2b 增强了 HeLa 细胞中 p21 蛋白的不稳定性。用蛋白酶体抑制剂 MG132 预处理细胞可消除 IFN-α2b 介导的 p21 降解，表明 IFN-α2b 加速了 p21 的泛素-蛋白酶体依赖性降解。与这些结果一致，IFN-α2b 增加了 HeLa 细胞中 S 期细胞周期分布。此外，IFN-α2b 通过 5-氟尿嘧啶（5-FU）从 G1 期阻滞和通过紫杉醇从 G2 期阻滞释放细胞。这些结果提供了 I 型 IFN 在细胞周期调控中的新作用，并可能定义了针对特定类型癌症的基于 IFN 的个体化治疗的重要性。
