Neoplasma. 2017;64(6):887-892. doi: 10.4149/neo_2017_610.
Most receptor tyrosine kinases (RTKs) contribute to tumor growth, and their ubiquitination and degradation is related to the inhibition of tumor growth. Our previous study showed that the ubiquitin ligase Cbl-b was expressed at low levels in multidrug-resistant (MDR) gastric cancer cells compared with their parental cells. However, whether enhancement of Cbl-b expression in MDR cancer cells could prevent tumor proliferation via ubiquitination and degradation of RTK remains unclear. In the present study, Cbl-b overexpression reduced cell proliferation in MDR gastric and breast cancer cells, and effectively inhibited tumor growth in vivo. Additionally, Cbl-b overexpression reduced the total protein level of insulin-like growth factor 1 (IGF-1R), an important member of the RTK family. Moreover, Cbl-b overexpression promoted interaction of Cbl-b with IGF-1R, and induced ubiquitination and degradation of IGF-1R and inactivation of the IGF-1R pathway. These results suggest that the ubiquitin ligase Cbl-b inhibited tumor growth via ubiquitination and degradation of IGF-1R in MDR gastric and breast cancer cells.
大多数受体酪氨酸激酶（RTKs）有助于肿瘤生长，其泛素化和降解与抑制肿瘤生长有关。我们之前的研究表明，与亲本细胞相比，多药耐药（MDR）胃癌细胞中的泛素连接酶 Cbl-b 表达水平较低。然而，MDR 癌细胞中 Cbl-b 表达的增强是否可以通过 RTK 的泛素化和降解来防止肿瘤增殖尚不清楚。在本研究中，Cbl-b 的过表达降低了 MDR 胃癌和乳腺癌细胞的增殖，并在体内有效抑制了肿瘤生长。此外，Cbl-b 的过表达降低了胰岛素样生长因子 1（IGF-1R）的总蛋白水平，IGF-1R 是 RTK 家族的重要成员。此外，Cbl-b 的过表达促进了 Cbl-b 与 IGF-1R 的相互作用，并诱导 IGF-1R 的泛素化和降解以及 IGF-1R 途径的失活。这些结果表明，泛素连接酶 Cbl-b 通过 MDR 胃癌和乳腺癌细胞中 IGF-1R 的泛素化和降解抑制肿瘤生长。
