The nuclear factor-κB pathway down-regulates expression of the NKG2D ligand H60a in vitro: implications for use of nuclear factor-κB inhibitors in cancer therapy.
The nuclear factor-κB pathway down-regulates expression of the NKG2D ligand H60a in vitro: implications for use of nuclear factor-κB inhibitors in cancer therapy.
复制标题
核因子-κB 通路在体外下调 NKG2D 配体 H60a 的表达：对在癌症治疗中使用核因子-κB 抑制剂的影响。
作者：
Peinado,Carlos;Kang,Xi;Hardamon,Chanae;Arora,Sumit;Mah,Stephen;Zhang,Hui;Ngolab,Jennifer;Bui,JackD
NKG2D配体是一种细胞表面蛋白，可以激活NKG2D，NKG2D是自然杀伤(NK)细胞用来检测病毒感染和转化细胞的受体。当肿瘤细胞表达高水平的NKG2D配体时，它们会被免疫系统排斥。因此，增加肿瘤细胞上NKG2D配体表达的试剂对于肿瘤免疫治疗是重要的。为了确定调控NKG2D配体H60a的基因，我们对3‘-甲基胆蒽诱导的肉瘤细胞株进行了高水平和低水平H60a表达的微阵列分析。核因子-κB(NF-κB)激活抑制因子A20在H60a-HI肉瘤细胞中有差异表达。相应地，用核因子-κB激活的抑制剂，如柳氮磺胺吡啶、BAY-11-7085或非磷酸化的I-κB处理肿瘤细胞，会导致H60a蛋白水平的增加，而转导具有活性形式的I-κB-β(IKKβ)的细胞会导致H60a蛋白水平的降低。这种调节可能发生在转录水平，因为抑制NF-κB途径导致H60a转录本和启动子活性增加。此外，SLZ对肿瘤细胞的体外杀伤作用增强了NK细胞的杀伤作用，提示抑制NF-κB可导致肿瘤细胞排斥反应。事实上，当我们阻断肿瘤细胞中的NF-κB通路时，野生型但没有免疫缺陷的小鼠的肿瘤生长减少。我们的结果表明，能够特异性地阻断肿瘤中的NF-κB活性的试剂，而不是宿主免疫细胞，将对肿瘤治疗有效。
NKG2D ligands are cell surface proteins that activate NKG2D, a receptor used by natural killer (NK) cells to detect virus‐infected and transformed cells. When tumour cells express high levels of NKG2D ligands, they are rejected by the immune system. Hence, reagents that increase NKG2D ligand expression on tumour cells can be important for tumour immunotherapy. To identify genes that regulate the NKG2D ligand H60a, we performed a microarray analysis of 3′‐methylcholanthrene‐induced sarcoma cell lines expressing high versus low H60a levels. A20, an inhibitor of nuclear factor‐κB (NF‐κB) activation, was differentially expressed in H60a‐hi sarcoma cells. Correspondingly, treatment of tumour cells with inhibitors of NF‐κB activation, such as sulfasalazine (slz), BAY‐11‐7085, or a non‐phosphorylatable IκB, led to increased levels of H60a protein, whereas transduction of cells with an active form of IκB kinase‐β (IKKβ) led to decreased levels of H60a. The regulation probably occurred at the transcriptional level, because NF‐κB pathway inhibition led to increased H60a transcripts and promoter activity. Moreover, treatment of tumour cells with slz enhanced their killing by NK cellsin vitro, suggesting that NF‐κB inhibition can lead to tumour cell rejection. Indeed, when we blocked the NF‐κB pathway specifically in tumour cells, there was decreased tumour growth in wild‐type but not immune‐deficient mice. Our results suggest that reagents that can block NF‐κB activity specifically in the tumour and not the host immune cells would be efficacious for tumour therapy.