Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL 33236, USA.
Oncol Rep. 2010 Mar;23(3):875-81.
Macrophages from mice bearing advanced mammary tumors are critically impaired in their immune functions, exhibiting reduced expression at the mRNA and protein levels of the crucial transcription factors, nuclear factor kappaB (NFkappaB) and CCAAT enhancer binding protein (C/EBP). We have previously shown that tumor-derived factors such as transforming growth factor beta (TGFbeta) and prostaglandin E2 (PGE2) modulate NFkappaB and C/EBP expression in macrophages. Transcriptional, post-transcriptional, translational and/or post-translational mechanisms may also play a role in altered levels of NFkappaB and C/EBP in macrophages from tumor hosts, contributing to impaired inflammatory response. One of the post-translational mechanisms that may tune down or recycle proteins in cells is the proteasomal pathway. Since upregulation of ubiquitin/proteasomal pathways has been described under cancer-induced cachexia, we examined the possible role of this proteolytic machinery in the decrease of NFkappaB and C/EBP proteins in macrophages from tumor hosts. Using MG-132 proteasome inhibitor to block the proteasome machinery in macrophages from normal and tumor-bearing animals we found that macrophages from tumor hosts display higher ubiquitination and proteolysis compared to those from normal mice and also that NFkappaB and C/EBP downregulation is reversed in these treated cells. Thus, proteasome degradation may contribute, at least in part, to NFkappaB and C/EBP impairment in macrophages from tumor-bearers.
患有晚期乳腺肿瘤的小鼠的巨噬细胞其免疫功能严重受损，其关键转录因子核因子 kappaB（NFkappaB）和 CCAAT 增强子结合蛋白（C/EBP）的 mRNA 和蛋白水平表达降低。我们之前已经表明，肿瘤衍生的因子，如转化生长因子 β（TGFbeta）和前列腺素 E2（PGE2），调节巨噬细胞中的 NFkappaB 和 C/EBP 表达。转录、转录后、翻译和/或翻译后机制也可能在肿瘤宿主来源的巨噬细胞中 NFkappaB 和 C/EBP 水平改变中发挥作用，导致炎症反应受损。一种可能下调或循环细胞中蛋白质的翻译后机制是蛋白酶体途径。由于泛素/蛋白酶体途径的上调已在癌症引起的恶病质中被描述，我们研究了这种蛋白水解机制在肿瘤宿主来源的巨噬细胞中 NFkappaB 和 C/EBP 蛋白减少中的可能作用。使用 MG-132 蛋白酶体抑制剂阻断正常和荷瘤动物巨噬细胞中的蛋白酶体机制，我们发现与来自正常小鼠的巨噬细胞相比，肿瘤宿主来源的巨噬细胞显示出更高的泛素化和蛋白水解，并且这些处理的细胞中的 NFkappaB 和 C/EBP 下调得到逆转。因此，蛋白酶体降解至少部分导致了肿瘤宿主来源的巨噬细胞中 NFkappaB 和 C/EBP 的损伤。
