Inhibiting β-Catenin by β-Carboline-Type MDM2 Inhibitor for Pancreatic Cancer Therapy.
Inhibiting β-Catenin by β-Carboline-Type MDM2 Inhibitor for Pancreatic Cancer Therapy.
复制标题
通过β-碳酸盐型MDM2抑制剂抑制β-catenin进行胰腺癌治疗。
DOI：
10.3389/fphar.2018.00005
复制
发表时间：
2018
影响因子：
5.6
通讯作者：
Zhang R
中科院分区：
文献类型：
--
作者：
Qin JJ;Wang W;Li X;Deokar H;Buolamwini JK;Zhang R
β-catenin和MDM 2癌蛋白在人胰腺癌中过表达并组成性激活，并有助于其发生、进展和转移。Wnt/β-catenin信号通路与MDM 2-p53信号通路相互作用，促进肿瘤的发生和发展。因此，抑制β-catenin和MDM 2的治疗被认为是晚期胰腺癌患者的理想治疗方法。我们最近鉴定了一类新的β-咔啉化合物作为特异性和有效的MDM 2抑制剂，包括先导化合物SP141。在本研究中，我们利用SP141作为示例性β-咔啉化合物来表征β-连环蛋白作为β-咔啉化合物的分子靶标，并证明β-连环蛋白在β-咔啉的抗癌活性中的重要作用。我们发现，β-catenin或MDM 2的沉默大大降低了SP141的抗癌活性，而两个基因的双重沉默几乎完全阻断了SP141的活性。在胰腺癌细胞中，SP141直接与β-catenin结合，并在体外和体内抑制其表达和活性。SP141对β-catenin的抑制作用是通过泛素-蛋白酶体系统介导的，且不依赖于MDM 2。总之，这些结果表明，SP141通过双重抑制β-连环蛋白和MDM 2发挥其抗癌活性。我们设想β-咔啉衍生物可以被开发为用于治疗晚期胰腺癌的有希望的β-连环蛋白和MDM 2的双重抑制剂。
The β-catenin and MDM2 oncoproteins are overexpressed and constitutively activated in human pancreatic cancer and contribute to its initiation, progression, and metastasis. The Wnt/β-catenin signaling pathway strongly interacts with the MDM2-p53 signaling pathway, accelerating the tumorigenesis and its development. Therefore, therapies inhibiting both β-catenin and MDM2 are suggested to be ideal treatments for patients with advanced pancreatic cancer. We have recently identified a novel class of β-carboline compounds as the specific and potent MDM2 inhibitors, including a lead compound SP141. In the present study, we utilized SP141 as an exemplary β-carboline compound to characterize β-catenin as a molecular target of the β-carboline compounds and to demonstrate an important role of β-catenin in the anticancer activity of β-carboline. We found that the silencing of either β-catenin or MDM2 largely reduced the anticancer activity of SP141 while the double silencing of both genes almost completely blocked SP141’s activity. SP141 directly bound to β-catenin and inhibited its expression and activity in pancreatic cancer cells in vitro and in vivo. The inhibitory effects of SP141 on β-catenin were mediated by the ubiquitin–proteasome system in an MDM2-independent manner. In conclusion, these results suggest that SP141 exerts its anticancer activity by dually inhibiting β-catenin and MDM2. We envision that β-carboline derivatives can be developed as promising dual inhibitors of β-catenin and MDM2 for the treatment of advanced pancreatic cancer.
登录
查看更多内容
影响因子：
4
作者：
Hobbs, G. Aaron;Der, Channing J.;Rossman, Kent L.
通讯作者：
Rossman, Kent L.
钛合金薄壁工件铣削过程阻尼建模及应用
影响因子：
1.6
作者：
Li, Xin;Zhao, Wei;Chi, ShengWei
通讯作者：
Chi, ShengWei
影响因子：
6.7
作者：
Joshi, Shrinivas D.;Dixit, Sheshagiri R.;Yang, Kap Seung
通讯作者：
Yang, Kap Seung
影响因子：
8.8
作者：
Hwang SY;Deng X;Byun S;Lee C;Lee SJ;Suh H;Zhang J;Kang Q;Zhang T;Westover KD;Mandinova A;Lee SW
通讯作者：
Lee SW
影响因子：
4.8
作者：
Orford, K;Crockett, C;Byers, SW
通讯作者：
Byers, SW