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
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.
Available from: PubMed Central
- "Similarly, the mechanisms regulating NCR expression on NK cells are not yet well understood . However, the study of  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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ABSTRACT: NK cells represent a potential tool for adoptive immunotherapy against tumors. Membrane-bound Hsp70 acts as a tumor-specific marker enhancing NK cell activity. Using flow cytometry the effect of in vitro stimulation with IL-2 or IL-15 alone or in combination with Hsp70-derived 14-mer peptide (TKD) on cell surface expression of NK activatory receptors (CD16, NKG2D, NKG2C, NKp46, NKp44, NKp30, KIR2DL4, DNAM-1, and LAMP1) and NK inhibitory receptors (NKG2A, KIR2DL2/L3, LIR1/ILT-2, and NKR-P1A) in healthy individuals was studied. Results were expressed as the percentage of receptor expressing cells and the amount of receptor expressed by CD3CD56 cellular population. CD94, NKG2D, NKp44, NKp30, KIR2DL4, DNAM-1, LAMP1, NKG2A, and NKR-P1A were upregulated after the stimulation with IL-2 or IL-15 alone or in combination with TKD. KIR2DL2/L3 was upregulated only by IL-15 and IL-15/TKD. Concurrently, an increase in a number of NK cells positive for CD94, NKp44, NKp30, KIR2DL4, and LAMP1 was observed. IL-15 and IL-15/TKD caused also cell number rise positive for KIR2DL2/L3 and NKR-P1A. Cell number positive for NKG2C and NKG2A was increased only by IL-2 and IL-2/TKD. The diverse effect of IL-2 or IL-15 w or w/o TKD on cell surface expression was observed in CD16, NKp46, and LIR1/ILT-2.
Mediators of Inflammation 02/2013; 2013(9):405295. DOI:10.1155/2013/405295 · 3.24 Impact Factor
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ABSTRACT: We report on the results of an experimental study of morpho-functional changes in the hippocampus after bilateral intracerebroventricular injection of β-amyloid peptide (Aβ 25–35) with and without intramuscular administration of proline-rich peptide (PRP)-1 and an isotonic solution of NaCl in the same regimen (administered 1 day before intoxication, 6 days after intoxication, and then every other day for a 4-week period), performed in six series of experiments on rats. Significant cellular neurodegeneration and almost full destruction of the dentate fascia were observed in almost all regions of the hippocampal complex of animals receiving Aβ 25–35. The neurodegeneration was accompanied by a marked glial reaction. Almost full restoration of the dentate fascia and all hippocampal gyri was achieved in animals regularly receiving PRP-1 after the injection of Aβ 25–35. We present the results of an electrophysiologic study of the changes in hippocampal evoked neuronal spike flow activity during the single and high-frequency (tetanic) stimulation of the entorhinal cortex of the ipsilateral cerebral hemisphere. Hippocampal neurons of intact animals responded to tetanic stimulation by tetanic and posttetanic potentiation of a different intensity and duration, which, in some cases, was accompanied by posttetanic depression. Under conditions of Aβ 25–35 intoxication, an obvious disparity in the level and form of hippocampal neuronal activity was revealed compared with the norm, which indicates an absence of the determined tetanic and posttetanic activities. There was a scant post-stimulus manifestation of activity along with an occasionally encountered effect, which rapidly decreased after repeated trials. This can also indicate the focal character of injury. The administration of PRP-1 for 1 month resulted in optimal prevention of intoxication and an actual return to normality. Furthermore, this administration maintained the initial learning level achieved in rats during a behavioral study in a Morris water maze. These findings suggest the possible therapeutic use of PRP-1 in the treatment of neurodegenerative diseases.
Available from: onlinelibrary.wiley.com
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ABSTRACT: A number of surface receptors expressed on NK cells are related to the regulation of NK cell activity and characterized by either inhibitory or activating properties. Natural cytotoxicity receptors (NCR) are one major family of activating receptors involved in NK cytotoxicity. The three family members of NCR are NKp46, NKp44, and NKp30. The surface density of these receptors might vary with the activation state of NK cells, and their density may directly correlate with their natural cytotoxicity. In this study, we investigated the regulation of NKp46 expression and determined the amino acid sequence motif for protein kinase C (PKC)-mediated regulation of its surface expression. We produced stable cell lines expressing full-length NKp46 and investigated the change in expression after PMA or IL-2 treatment using flow cytometry, RT-PCR, and immunoblotting methods. Expression of NKp46 on Jurkat T-cell transfectants appeared to be induced by PMA treatment until 8-h post-treatment and then gradually decreased afterwards to levels that were less than those measured at pretreatment. Parallel to surface expression of NKp46, total NKp46 protein expression also appeared to fluctuate after PMA treatment, but the expression of mRNA transcripts was not significantly affected. Experiments with mutant NKp46-expressing stable cell lines demonstrated that Ser288 might be critical for the surface expression of NKp46 and the PKC-mediated regulation of NKp46 expression. However, NKp46 surface expression was not influenced by IL-2 in stable cell lines expressing wild-type and mutant NKp46.
Scandinavian Journal of Immunology 06/2010; 71(6):413-9. DOI:10.1111/j.1365-3083.2010.02395.x · 1.74 Impact Factor
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