Anti-cancer activity and mechanistic features of a NK cell activating molecule

Brain Korea 21 Project for Medical Sciences, Department of Microbiology, Yonsei University College of Medicine, Seoul, Korea.
Cancer Immunology and Immunotherapy (Impact Factor: 3.94). 04/2009; 58(10):1691-700. DOI: 10.1007/s00262-009-0680-0
Source: PubMed


Natural cytotoxicity receptors (NCRs) are major activating receptors involved in NK cytotoxicity. NCR expression varies with the activation state of NK cells, and the expression level correlates with NK cells' natural cytotoxicity. In this study, we found that Gö6983, a PKC inhibitor, induced a remarkable increase of NCR expression on primary NK cells, but other PKC inhibitors and NK cell stimulators such as IL-2 and PMA, did not. Gö6983 increased the expression of NCR in a time- and concentration-dependent manner. Furthermore, Gö6983 strongly upregulated the surface expression of death ligands FasL and TRAIL, but not cytotoxic molecules perforin and granzyme B. Unlike two other NK stimulating molecules, IL-2, and PMA, Gö6983 did not induce NK cell proliferation. Up-regulation of NCRs and death ligands on NK cells by Gö6983 resulted in a significant enhancement of NK cytotoxicity against various cancer cell lines. Most importantly, administration of Gö6983 effectively inhibited pulmonary tumor metastasis in mice in a dose-dependent manner. These results suggest that Gö6983 functions as an NK cell activating molecule (NKAM); this NKAM is a novel anti-cancer and anti-metastasis drug candidate because it enhances NK cytotoxicity against cancer cells in vivo as well as in vitro.

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    • "Similarly, the mechanisms regulating NCR expression on NK cells are not yet well understood [37]. However, the study of [38] has demonstrated the possibility that NCR expression could also be regulated by PKC in NK cells. Prolactin induces upregulation of NCR expression augmenting NK cytotoxicity against tumour cells, and vice versa corticosteroids or TGF-β1 reduces NK cytotoxicity [39, 40]. "
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