Ribonuclease inhibitor up-regulation inhibits the growth and induces apoptosis in murine melanoma cells through repression of angiogenin and ILK/PI3K/AKT signaling pathway
Ribonuclease inhibitor up-regulation inhibits the growth and induces apoptosis in murine melanoma cells through repression of angiogenin and ILK/PI3K/AKT signaling pathway
复制标题
核糖核酸酶抑制剂上调通过抑制血管生成素和 ILK/PI3K/AKT 信号通路抑制小鼠黑色素瘤细胞的生长并诱导细胞凋亡
DOI：
10.1016/j.biochi.2014.04.007
复制
发表时间：
2014-08-01
期刊：
影响因子：
3.9
通讯作者：
Chen, Jun-Xia
中科院分区：
文献类型：
--
作者：
Li, Lin;Pan, Xiang-Yang;Chen, Jun-Xia
人核糖核酸酶抑制剂（RI）是一种细胞质蛋白，几乎完全由富含亮氨酸的重复序列构成。RI与核糖核酸酶和血管生成素（ANG）紧密结合，抑制其活性。ANG是一种有效的血管生长诱导剂，与肿瘤的形成、生长和转移有关。ILK/PI3K/AKT信号通路在细胞生长、细胞周期进展、肿瘤血管生成、细胞凋亡等过程中也发挥着重要作用。我们之前的实验表明，RI可能有效地抑制一些肿瘤的生长和转移。我们最近的研究表明，ILK siRNA抑制膀胱癌细胞的生长并诱导凋亡，增加RI的表达，这表明RI与ILK之间存在相关性。然而，RI在抗肿瘤和ANG与ILK信号通路串扰中的确切分子机制仍不清楚。本研究通过血管生成素和ILK/PI3K/AKT信号通路研究上调RI对小鼠黑色素瘤细胞生长和凋亡的影响。我们发现，上调RI可明显降低ANG的表达和活性。我们还发现，RI过表达可以显著抑制细胞增殖，调节细胞周期，诱导细胞凋亡。此外，RI的上调抑制了ILK下游信号靶蛋白激酶B/Akt、糖原合成酶激酶3- β (GSK-3 β)的磷酸化，降低了体内和体外β -连环蛋白的表达。更重要的是，RI显著抑制了荷瘤C57BL/6小鼠的肿瘤生长和血管生成。总之，我们的研究结果首次提示血管生成素和ILK信号通路在介导RI对黑色素瘤细胞生长的抑制作用中起关键作用。本研究确定RI可能是黑色素瘤治疗的一个有用的分子靶点。(C) 2014 Elsevier Masson SAS。版权所有。
Human ribonuclease inhibitor (RI), a cytoplasmic protein, is constructed almost entirely of leucine rich repeats. RI could suppress activities of ribonuclease and angiogenin (ANG) through closely combining with them. ANG is a potent inducer of blood vessel growth and has been implicated in the establishment, growth, and metastasis of tumors. ILK/PI3K/AKT signaling pathway also plays important roles in cell growth, cell-cycle progression, tumor angiogenesis, and cell apoptosis. Our previous experiments demonstrated that RI might effectively inhibit some tumor growth and metastasis. Our recent study showed that ILK siRNA inhibited the growth and induced apoptosis in bladder cancer cells as well as increased RI expression, which suggest a correlation between RI and ILK. However, the exact molecular mechanism of RI in anti-tumor and in the cross-talk of ANG and ILK signaling pathway remains largely unknown. Here we investigated the effects of up-regulating RI on the growth and apoptosis in murine melanoma cells through angiogenin and ILK/PI3K/AKT signaling pathway. We demonstrated that up-regulating RI obviously decreased ANG expression and activity. We also discovered that RI over-expression could remarkably inhibit cell proliferation, regulate cell cycle and induce apoptosis. Furthermore, up-regulation of RI inhibited phosphorylation of ILK downstream signaling targets protein kinase B/Akt, glycogen synthase kinase 3-beta (GSK-3 beta), and reduced beta-catenin expression in vivo and vitro. More importantly, RI significant inhibited the tumor growth and angiogenesis of tumor bearing C57BL/6 mice. In conclusion, our findings, for the first time, suggest that angiogenin and ILK signaling pathway plays a pivotal role in mediating the inhibitory effects of RI on melanoma cells growth. This study identifies that RI may be a useful molecular target for melanoma therapy. (C) 2014 Elsevier Masson SAS. All rights reserved.