Apigenin: Selective CK2 inhibitor increases Ikaros expression and improves T cell homeostasis and function in murine pancreatic cancer.
Apigenin: Selective CK2 inhibitor increases Ikaros expression and improves T cell homeostasis and function in murine pancreatic cancer.
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DOI：
10.1371/journal.pone.0170197
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Ghansah T
中科院分区：
文献类型：
--
作者：
Nelson N;Szekeres K;Iclozan C;Rivera IO;McGill A;Johnson G;Nwogu O;Ghansah T
胰腺癌（PC）通过促进抑制效应T细胞的调节性T细胞（Tregs）的发展来逃避免疫破坏。转录因子Ikaros对淋巴细胞，尤其是T细胞的发育至关重要。我们之前已经在我们的Panc02荷瘤（TB）小鼠模型中表明，Ikaros的下调是其蛋白质被泛素-蛋白酶体系统降解的结果。在机制上，我们观察到酪蛋白激酶II （CK2）和蛋白磷酸酶1 （PP1）之间平衡的解除，这表明在我们的模型中，CK2活性的增加负责调节Ikaros的稳定性。我们还发现Ikaros表达的缺失与TB小鼠中CD4+和CD8+ T细胞百分比的显著降低以及CD4+CD25+ Tregs细胞百分比的增加有关。在这项研究中，我们评估了饲料中添加黄酮类芹菜素（API）对Ikaros表达和T细胞免疫反应的影响。用（API）处理naïve小鼠脾细胞稳定了Ikaros的表达，并在体外阻止了小鼠Panc02细胞存在下Ikaros的下调，类似于蛋白酶体抑制剂MG132。在体内用芹菜素（TB- api）治疗结核小鼠可提高生存率，减轻肿瘤重量并防止脾肿大。API治疗还恢复了一些Ikaros亚型的蛋白表达，这可能归因于其对结核-API小鼠脾细胞CK2活性的适度抑制。在TB-API小鼠中，Ikaros表达的部分恢复伴随着CD4+和CD8+ T细胞百分比的显著增加和Treg百分比的降低。此外，与TB小鼠相比，TB- api小鼠的CD8+ T细胞产生更多的IFN-γ，其脾细胞能够更好地启动异体CD8+ T细胞反应。这些结果进一步证明了胰腺癌模型中Ikaros受CK2调控。更重要的是，我们的研究结果表明API可能是一种稳定Ikaros表达和维持小鼠PC中T细胞稳态的功能的可能的治疗剂。
Pancreatic cancer (PC) evades immune destruction by favoring the development of regulatory T cells (Tregs) that inhibit effector T cells. The transcription factor Ikaros is critical for lymphocyte development, especially T cells. We have previously shown that downregulation of Ikaros occurs as a result of its protein degradation by the ubiquitin-proteasome system in our Panc02 tumor-bearing (TB) mouse model. Mechanistically, we observed a deregulation in the balance between Casein Kinase II (CK2) and protein phosphatase 1 (PP1), which suggested that increased CK2 activity is responsible for regulating Ikaros’ stability in our model. We also showed that this loss of Ikaros expression is associated with a significant decrease in CD4+ and CD8+ T cell percentages but increased CD4+CD25+ Tregs in TB mice. In this study, we evaluated the effects of the dietary flavonoid apigenin (API), on Ikaros expression and T cell immune responses. Treatment of splenocytes from naïve mice with (API) stabilized Ikaros expression and prevented Ikaros downregulation in the presence of murine Panc02 cells in vitro, similar to the proteasome inhibitor MG132. In vivo treatment of TB mice with apigenin (TB-API) improved survival, reduced tumor weights and prevented splenomegaly. API treatment also restored protein expression of some Ikaros isoforms, which may be attributed to its moderate inhibition of CK2 activity from splenocytes of TB-API mice. This partial restoration of Ikaros expression was accompanied by a significant increase in CD4+ and CD8+ T cell percentages and a reduction in Treg percentages in TB-API mice. In addition, CD8+ T cells from TB-API mice produced more IFN-γ and their splenocytes were better able to prime allogeneic CD8+ T cell responses compared to TB mice. These results provide further evidence that Ikaros is regulated by CK2 in our pancreatic cancer model. More importantly, our findings suggest that API may be a possible therapeutic agent for stabilizing Ikaros expression and function to maintain T cell homeostasis in murine PC.