Olcina Monica M, Kim Ryan K, Balanis Nikolas G, Li Caiyun Grace, von Eyben Rie, Graeber Thomas G, Ricklin Daniel, Stucki Manuel, Giaccia Amato J
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.
Department of Gynecology, University of Zurich, Wagistrasse 14, 8952 Schlieren, Switzerland.
iScience. 2020 Sep 21;23(10):101594. doi: 10.1016/j.isci.2020.101594. eCollection 2020 Oct 23.
The importance of innate immunity in cancer is increasingly being recognized with recent reports suggesting tumor cell-intrinsic intracellular functions for innate immunity proteins. However, such functions are often poorly understood, and it is unclear whether these are affected by patient-specific mutations. Here, we show that C4b-binding protein alpha chain (C4BPA), typically thought to reside in the extracellular space, is expressed intracellularly in cancer cells, where it interacts with the NF-κB family member RelA and regulates apoptosis. Interestingly, intracellular C4BPA expression is regulated in a stress- and mutation-dependent manner and mutations are associated with improved cancer survival outcome. Using cell lines harboring patient-specific mutations, we show that increasing intracellular C4BPA levels correlate with sensitivity to oxaliplatin-induced apoptosis and . Mechanistically, sensitive mutants display increased IκBα expression and increased inhibitory IκBα-RelA complex stability. These data suggest a non-canonical intracellular role for C4BPA in regulating NF-κB-dependent apoptosis.
随着最近的报告表明先天免疫蛋白具有肿瘤细胞内在的细胞内功能，先天免疫在癌症中的重要性越来越受到认可。然而，这些功能通常了解甚少，并且尚不清楚它们是否受患者特异性突变的影响。在这里，我们表明，通常被认为存在于细胞外空间的C4b结合蛋白α链（C4BPA）在癌细胞内表达，在那里它与NF-κB家族成员RelA相互作用并调节细胞凋亡。有趣的是，细胞内C4BPA的表达以应激和突变依赖的方式受到调节，并且突变与改善的癌症生存结果相关。使用携带患者特异性突变的细胞系，我们表明增加细胞内C4BPA水平与对奥沙利铂诱导的细胞凋亡的敏感性相关。从机制上讲，敏感突变体显示IκBα表达增加以及抑制性IκBα-RelA复合物稳定性增加。这些数据表明C4BPA在调节NF-κB依赖性细胞凋亡中具有非经典的细胞内作用。
