Interferon-α2b induces p21cip1/waf1 degradation and cell proliferation in HeLa cells
Interferon-α2b induces p21cip1/waf1 degradation and cell proliferation in HeLa cells
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DOI：
10.4161/cc.9.1.10250
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发表时间：
2010-01-01
期刊：
影响因子：
4.3
通讯作者：
Satoh, Kei
中科院分区：
文献类型：
--
作者：
Ota, Ken;Matsumiya, Tomoh;Satoh, Kei
I型干扰素（IFN）是表现出各种生物活性的细胞因子家族。除了它们在免疫应答中的作用之外，已知IFN调节细胞增殖和诱导细胞凋亡。因此，IFN被用作针对某些类型的癌症的抗肿瘤剂，但目前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-α 2b，IFN-α的一个亚家族，增强了HeLa细胞的增殖，HeLa细胞是一种来自人类宫颈癌的细胞系。IFN-α 2b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。在增殖和凋亡相关基因中，p21（cip 1/waf 1）（p21）被IFN-α 2b上调，而p53、p27或BCL-2相关X蛋白（BAX）不受影响。IFN-alpha 2b不会改变p21启动子活性，但确实延长了p21 mRNA的衰变。相反，IFN-α 2b降低p21蛋白的水平，并且p21蛋白的半衰期分析显示IFN-α 2b增强HeLa细胞中p21蛋白的不稳定性。用蛋白酶体抑制剂MG 132预处理细胞，消除了IFN-α 2b介导的p21降解，表明IFN-α 2b加速了p21的泛素-蛋白酶体依赖性降解。与这些结果一致，IFN-α 2b增加HeLa细胞中的S期细胞周期分布。此外，IFN-α 2b将细胞从5-氟尿嘧啶（5-FU）的G（1）期阻滞和紫杉醇的G（2）期阻滞中解放出来。这些结果提供了一个新的作用，I型干扰素在细胞周期调控，并可能定义一个重要的个性化干扰素为基础的治疗对特定类型的癌症。
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-alpha 2b, a subfamily of IFN-alpha, enhanced proliferation of HeLa cells, a cell line derived from human cervical cancer. IFN-alpha 2b 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-alpha 2b, whereas p53, p27 or BCL-2 associated X protein (BAX) was not affected. IFN-alpha 2b 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-alpha 2b, and half-life analysis of p21 protein revealed that IFN-alpha 2b enhances p21 protein instability in HeLa cells. Pretreatment of the cells with MG132, a proteasome inhibitor, abolished the IFN-alpha 2b-mediated p21 degradation, suggesting that IFN-alpha 2b accelerated the ubiquitin-proteasome dependent degradation of p21. Consistent with these results, IFN-alpha 2b increased S-phase cell cycle distribution in HeLa cells. In addition, IFN-alpha 2b 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.