Wu Bo, Liu Zhen-Yu, Cui Jian, Yang Xiang-Min, Jing Lin, Zhou Yang, Chen Zhi-Nan, Jiang Jian-Li
National Translational Science Center for Molecular Medicine, Cell Engineering Research Center & Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China.
Int J Mol Sci. 2017 Jan 20;18(1):212. doi: 10.3390/ijms18010212.
Drug resistance remains a major clinical obstacle to successful treatment of cancer. As posttranslational modification is becoming widely recognized to affect the function of oncoproteins, targeting specific posttranslational protein modification provides an attractive strategy for anticancer drug development. CD147 is a transmembrane glycoprotein contributing to chemo-resistance of cancer cells in a variety of human malignancies. Ubiquitination is an important posttranslational modification mediating protein degradation. Degradation of oncoproteins, CD147 included, emerges as an attractive alternative for tumor inhibition. However, the ubiquitination of CD147 remains elusive. Here in this study, we found that deletion of the CD147 intracellular domain (CD147-ICD) prolonged the half-life of CD147 in HEK293T cells, and we identified that CD147-ICD interacts with FBXO22 using mass spectrometry and Western blot. Then, we demonstrated that FBXO22 mediates the polyubiquitination and degradation of CD147 by recognizing CD147-ICD. While knocking down of FBXO22 prolonged the half-life of CD147 in HEK293T cells, we found that FBXO22 regulates CD147 protein turnover in SMMC-7721, Huh-7 and A549 cells. Moreover, we found that the low level of FBXO22 contributes to the accumulation of CD147 and thereafter the cisplatin resistance of A549/DDP cells. To conclude, our study demonstrated that FBXO22 mediated the polyubiquitination and degradation of CD147 by interacting with CD147-ICD, and CD147 polyubiquitination by FBXO22 reversed cisplatin resistance of tumor cells.
耐药性仍然是癌症成功治疗的主要临床障碍。由于翻译后修饰对癌蛋白功能的影响已得到广泛认可，靶向特定的翻译后蛋白修饰为抗癌药物开发提供了一个有吸引力的策略。CD147是一种跨膜糖蛋白，在多种人类恶性肿瘤中导致癌细胞的化疗耐药性。泛素化是介导蛋白质降解的一种重要翻译后修饰。包括CD147在内的癌蛋白降解成为一种有吸引力的肿瘤抑制替代方法。然而，CD147的泛素化情况仍然不清楚。在本研究中，我们发现缺失CD147细胞内结构域（CD147-ICD）可延长CD147在HEK293T细胞中的半衰期，并且我们通过质谱和蛋白质印迹鉴定出CD147-ICD与FBXO22相互作用。然后，我们证明FBXO22通过识别CD147-ICD介导CD147的多聚泛素化和降解。虽然敲低FBXO22可延长CD147在HEK293T细胞中的半衰期，但我们发现FBXO22调节SMMC-7721、Huh-7和A549细胞中CD147的蛋白质周转。此外，我们发现FBXO22水平低导致CD147积累，进而导致A549/DDP细胞对顺铂耐药。总之，我们的研究表明FBXO22通过与CD147-ICD相互作用介导CD147的多聚泛素化和降解，并且FBXO22介导的CD147多聚泛素化可逆转肿瘤细胞的顺铂耐药性。
