Abstract
In this study, we have investigated if current cancer therapeutic modalities including hyperthermia and ionizing radiation can increase the expression of NKG2D ligands in human cancer cell lines. The expressions of NKG2D ligands were induced by both heat shock and ionizing radiation in various cell lines including KM12, NCI-H23, HeLa and A375 cells with peaks at 2 h and 9 h after treatment, respectively, although inducibility of each NKG2D ligand was various depending on cell lines. During the induction of NKG2D ligands, heat shock protein 70 was induced by heat shock but not by ionizing radiation. These results were followed by increased susceptibilities to NK cell-mediated cytolysis after treatment with heat shock and ionizing radiation. These results suggest that heat shock and ionizing radiation induce NKG2D ligands and consequently might lead to increased NK cell-mediated cytotoxicity in various cancer cells.
Highlights
Based on the discovery and identification of tumorassociated antigens, it is possible to target tumors by cytotoxic T lymphocytes (CTLs) (Rosenberg, 1999)
Since recent findings illustrated that NK cell activation via NKG2D receptor can occur despite the normal expression of major histocompatibility complex (MHC) class I molecules on the target cells (Cerwenka et al, 2000; Diefenbach et al, 2000; O'Connor et al, 2006), stress-induced upregulation of NKG2D ligands in tumor cells may trigger an additional signal towards activation and induction of NK cell-mediated cytolysis (Biassoni et 6 h 9 h 12 h 24 h al., 2003)
We have shown that heat shock upregulated expression of UL-16 binding proteins (ULBPs) and ionizing radiation increased the expression of NKG2D ligands in various human cancer cell lines, and increased their susceptibility to NK cell-mediated cytotoxicity
Summary
Based on the discovery and identification of tumorassociated antigens, it is possible to target tumors by cytotoxic T lymphocytes (CTLs) (Rosenberg, 1999). Tumors lacking MHC class I expression become more susceptible to NK cells (Pawelec, 2004). NK cell-mediated killing of tumor cells is result of integration of signals from several activating and inhibitory receptors that are regulated by the density and selection of class I and class-I like ligands expressed by the target cell (Farag et al, 2003). The best characterized activating ligands are the NKG2D ligands, in which MHC class I-related chain A and B (MICA/B) have been known to be induced by cellular distresses such as heat shock, oxidative stress and viral infection, and UL-16 binding proteins (ULBPs) by viral infection (Vivier et al, 2002; Farag and Caligiuri, 2006). Feature of the different NKG2D ligands is their stress-inducible expression and their specific presence on different tumor cell lines (Watzl, 2003)
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