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

Abstract

SummaryNKG2D 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-jB (NF-jB) activation, was differentially expressed in H60a-hi sarcoma cells. Correspondingly, treatment of tumour cells with inhibitors of NF-jB activation, such as sulfasalazine (slz), BAY-11-7085, or a non-phosphorylatable IjB, led to increased levels of H60a protein, whereas transduction of cells with an active form of IjB kinase-b (IKKb) led to decreased levels of H60a. The regulation probably occurred at the transcriptional level, because NF-jB pathway inhibition led to increased H60a transcripts and promoter activity. Moreover, treatment of tumour cells with slz enhanced their killing by NK cells in vitro, suggesting that NF-jB inhibition can lead to tumour cell rejection. Indeed, when we blocked the NF-jB 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-jB activity specifically in the tumour and not the host immune cells would be efficacious for tumour therapy.

Upregulation of Myc promotes the evasion of NK cell‑mediated immunity through suppression of NKG2D ligands in K562 cells

“…Except BCR/ABL, which induces the expression of NKG2D ligands (14), inhibition of several oncogenes including Ras, EGFR, NF-κB, and Akt can induce the expression of NKG2D ligands, therefore, it was thought that these oncogenes might contribute to immune escape of cancer cells (13,15,16). However, it remains to be addressed whether c-Myc could modulate the expression of NKG2D ligands.…”

“…Since aberrant expression of c-Myc oncogenes changes the expression of many other genes, and maintains malignancy in cancer cells, it was suspected that c-Myc might disturb NK cell-mediated immune responses through the altered expression of several genes, such as those encoding NKG2D ligands. Previously, it was revealed that inhibition of several oncogenes, such as EGFR, PI3K, Ras, NF-κB and BCR/ABL, could modulate the expression of NKG2D ligands (13–16). In this study, we investigated whether c-Myc modulates the expression of NKG2D ligands and affects the susceptibility of cancer cells to NK cells.…”

IκB kinase α functions as a tumor suppressor in epithelial-derived tumors through an NF-κB-independent pathway (Review)

“…Studies have demonstrated that IKKα mutations are present in human SCC and that a marked reduction in IKKα expression occurs in poorly differentiated human and mouse cutaneous SCCs (18). In studies of chemical carcinogen-induced (19) or UVB-induced (20)(21)(22) skin carcinogenesis, the findings have shown that lack of IKKα expression promotes the development of skin papillomas and carcinomas in IKKα +/mice. In chemical carcinogen-induced skin carcinogenesis, reduced levels of IKKα promote the oncogenic H-Ras pathway and enhance the mitogenic activity, extracellular signal-regulated kinase (ERK) activity and overexpression of growth factors (19); and in addition, influence UVB-related p53 mutations, upregulate the expression of monocyte chemoattractant protein-1 (MCP-1/ CCL2), TNF-α, IL-1 and elevate macrophage migration, which are crucial for accelerating uVB skin carcinogenesis (21,23).…”