Activation of human natural killer cells by the soluble form of cellular prion protein

Seong, Yeon-Jae; Sung, Pil Soo; Jang, Yongwon; Choi, Young Joon; Park, Bum-Chan; Park, Su–Hyung; Park, Young Woo; Shin, Eui‐Cheol

doi:10.1016/j.bbrc.2015.06.172

Cited by 9 publications

(8 citation statements)

References 27 publications

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“…Thus, various soluble recombinant forms of PrP C bound to and underwent partial LRP/LR-dependent internalization (Gauczynski et al, 2001), protected human neurons from Bax-mediated apoptosis (Bounhar et al, 2001), induced neurite outgrowth and/or synaptogenesis in cultured cerebellar and hippocampal neurons (Chen et al, 2003; Kanaani et al, 2005), and activated monocytes (Krebs et al, 2006; Jeon et al, 2013) and natural killer cells (Seong et al, 2015). Such effects are contingent upon the activation of a variety of intracellular signaling molecules, including PI3-kinase, Erk, cAMP/PKA or PKC (for review see Linden et al, 2008).…”

Section: The Prion Protein As a Cell Surface Scaffold Proteinmentioning

confidence: 99%

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

Linden

2017

Front. Mol. Neurosci.

115

104

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The prion glycoprotein (PrPC) is mostly located at the cell surface, tethered to the plasma membrane through a glycosyl-phosphatydil inositol (GPI) anchor. Misfolding of PrPC is associated with the transmissible spongiform encephalopathies (TSEs), whereas its normal conformer serves as a receptor for oligomers of the β-amyloid peptide, which play a major role in the pathogenesis of Alzheimer’s Disease (AD). PrPC is highly expressed in both the nervous and immune systems, as well as in other organs, but its functions are controversial. Extensive experimental work disclosed multiple physiological roles of PrPC at the molecular, cellular and systemic levels, affecting the homeostasis of copper, neuroprotection, stem cell renewal and memory mechanisms, among others. Often each such process has been heralded as the bona fide function of PrPC, despite restricted attention paid to a selected phenotypic trait, associated with either modulation of gene expression or to the engagement of PrPC with a single ligand. In contrast, the GPI-anchored prion protein was shown to bind several extracellular and transmembrane ligands, which are required to endow that protein with the ability to play various roles in transmembrane signal transduction. In addition, differing sets of those ligands are available in cell type- and context-dependent scenarios. To account for such properties, we proposed that PrPC serves as a dynamic platform for the assembly of signaling modules at the cell surface, with widespread consequences for both physiology and behavior. The current review advances the hypothesis that the biological function of the prion protein is that of a cell surface scaffold protein, based on the striking similarities of its functional properties with those of scaffold proteins involved in the organization of intracellular signal transduction pathways. Those properties are: the ability to recruit spatially restricted sets of binding molecules involved in specific signaling; mediation of the crosstalk of signaling pathways; reciprocal allosteric regulation with binding partners; compartmentalized responses; dependence of signaling properties upon posttranslational modification; and stoichiometric requirements and/or oligomerization-dependent impact on signaling. The scaffold concept may contribute to novel approaches to the development of effective treatments to hitherto incurable neurodegenerative diseases, through informed modulation of prion protein-ligand interactions.

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Section: The Prion Protein As a Cell Surface Scaffold Proteinmentioning

confidence: 99%

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

Linden

2017

Front. Mol. Neurosci.

115

104

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“…Peripheral blood mononuclear cells (PBMCs) from adult healthy donors were isolated using Ficoll-Hypaque density gradient centrifugation as previously described. 27 NK cells were separated from PBMCs using the OctoMACS starting kit (Miltenyi Biotec, Auburn, CA, USA) as described previously. 27 The hepatoma cells were cultured in a 24-well plate for 24 hours.…”

Section: Cytotoxicity and Degranulation Assaymentioning

confidence: 99%

“…27 NK cells were separated from PBMCs using the OctoMACS starting kit (Miltenyi Biotec, Auburn, CA, USA) as described previously. 27 The hepatoma cells were cultured in a 24-well plate for 24 hours. Then, isolated human NK cells were added at different effector-to-target ratios.…”

Section: Cytotoxicity and Degranulation Assaymentioning

confidence: 99%

EpCAM-high liver cancer stem cells resist natural killer cell–mediated cytotoxicity by upregulating CEACAM1

Park

Sung

Kim

et al. 2020

J Immunother Cancer

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BackgroundNatural killer (NK) cells can recognize and kill cancer cells directly, but their activity can be attenuated by various inhibitory molecules expressed on the surface. The expression of epithelial cell adhesion molecule (EpCAM), a potential marker for cancer stem cells (CSCs), is known to be strongly associated with poor clinical outcomes in hepatocellular carcinoma (HCC). NK cells targeting CSCs may be a promising strategy for anti-tumor therapy, but little is known about how they respond to EpCAMhighCSCs in HCC.MethodsEpCAM expression was assessed by immunohistochemistry in 280 human HCC tissues obtained from curative surgery. To investigate the functional activity of NK cells against liver CSCs, EpCAMhighand EpCAMlowHuh-7 cells were sorted by flow cytometry. The functional role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which is related to NK cells, was determined by in vitro co-culture of NK cells and hepatoma cells using Hepa1–6 mouse hepatoma cells, as well as in vivo experiments using C57/BL6 mice.ResultsThe frequency of recurrence after curative surgery was higher in patients with positive EpCAM expression than in those with negative EpCAM expression. In subsequent analysis based on the anatomical location of EpCAM expression, patients with peritumoral EpCAM expression showed worse prognosis than those with pantumoral EpCAM expression. Co-culture experiments demonstrated that CEACAM1 was upregulated on the surface of EpCAMhighHCC cells, resulting in resistance to NK cell-mediated cytotoxicity. Inversely, silencing CEACAM1 restored cytotoxicity of NK cells against EpCAMhighHuh-7 cells. Moreover, neutralizing CEACAM1 on the NK cell surface enhanced killing of Huh-7 cells, suggesting that homophilic interaction of CEACAM1 is responsible for attenuated NK cell–mediated killing of CEACAM1highcells. In mouse experiments with Hepa1–6 cells, EpCAMhighHepa1–6 cells formed larger tumors and showed higher CEACAM1 expression after NK cell depletion. NK-mediated cytotoxicity was enhanced after blocking CEACAM1 expression using the anti-CEACAM1 antibody, thereby facilitating tumor regression. Moreover, CEACAM1 expression positively correlated with EpCAM expression in human HCC tissues, and serum CEACAM1 levels were also significantly higher in patients with EpCAM+HCC.ConclusionOur data demonstrated that EpCAMhighliver CSCs resist NK cell–mediated cytotoxicity by upregulation of CEACAM1 expression.

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“…Amongst them, the CD56 dim NK cells constitute approximately 90% of the total NK cells, show mature phenotype, and mediate cytolytic reactions. In contrast, the immature CD56 bright NK cells constitute 5% to 15% of the total NK cells and have been regarded as cytokine producers (21,22). The most important cytolytic targets of NK cells are the abnormal cells having the downregulated expression of the major histocompatibility complex (MHC) class I, which is highly expressed on the surface of most of the healthy, nucleated cells (23).…”

Section: Biology Of Human Nk Cellsmentioning

confidence: 99%

Natural Killer Cell Dysfunction in Hepatocellular Carcinoma: Pathogenesis and Clinical Implications

Sung

Jang

2018

Preprint

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Hepatocellular carcinoma (HCC) is currently the third leading cause of malignancy-related mortalities worldwide. Natural killer (NK) cells are involved in the critical role of first line immunological defense against cancer development. Defects in NK cell functions are recognized as important mechanisms for immune evasion of tumor cells. NK cell function appears to be attenuated in HCC, and many previous reports suggested that NK cells play a critical role in controlling HCC, suggesting that boosting the activity of dysfunctional NK cells can enhance tumor cell killing. However, the detailed mechanisms of NK cell dysfunction in tumor microenvironment of HCC remain largely unknown. A better understanding of the mechanisms of NK cell dysfunction in HCC will help in the NK cell-mediated eradication of cancer cells and prolong patient survival. In this review, we describe the various mechanisms underlying NK cell dysfunction in HCC. Further, we summarize current advances in the approaches to enhance endogenous NK cell function and in adoptive NK cell therapies, to cure this difficult-to-treat cancer.

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Activation of human natural killer cells by the soluble form of cellular prion protein

Cited by 9 publications

References 27 publications

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

EpCAM-high liver cancer stem cells resist natural killer cell–mediated cytotoxicity by upregulating CEACAM1

Natural Killer Cell Dysfunction in Hepatocellular Carcinoma: Pathogenesis and Clinical Implications

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