Anti-cancer activity and mechanistic features of a NK cell activating molecule.
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.
Kim
Hyung-Ran
HR
Brain Korea 21 Project for Medical Sciences, Department of Microbiology, Yonsei University College of Medicine, Seoul, Korea.
Lee
Kyoung-Ho
KH
Park
Su Jung
SJ
Kim
So Young
SY
Yang
Young Keun
YK
Tae
Jinsung
J
Kim
Jongsun
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008113:Liver Neoplasms / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary; D008301:Maleimides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000235:genetics / Q000378:metabolism; D055629:Natural Cytotoxicity Triggering Receptor 2 / Q000235:genetics / Q000378:metabolism; D055628:Natural Cytotoxicity Triggering Receptor 3 / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D014407:Tumor Cells, Cultured
C465664:2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D053222:Fas Ligand Protein; D007211:Indoles; D008301:Maleimides; C112260:NCR1 protein, human; C112837:NCR2 protein, human; C431710:NCR3 protein, human; D055627:Natural Cytotoxicity Triggering Receptor 1; D055629:Natural Cytotoxicity Triggering Receptor 2; D055628:Natural Cytotoxicity Triggering Receptor 3; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D011493:Protein Kinase C