scholarly journals Complement-Mediated Selective Tumor Cell Lysis Enabled by Bi-Functional RNA Aptamers

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 86
Author(s):  
Prabhat K. Mallik ◽  
Kimi Nishikawa ◽  
Pramit Mallik ◽  
Hua Shi
Keyword(s):  
Cancer Cells ◽  
Membrane Attack Complex ◽  
Rna Aptamers ◽  
Mouse Serum ◽  
Complement Protein ◽  
A Cell ◽  
Target Molecules ◽  
Molecular Adaptors ◽  
Tumor Cell Lysis ◽  
Effector Mechanisms

Unlike microbes that infect the human body, cancer cells are descended from normal cells and are not easily recognizable as “foreign” by the immune system of the host. However, if the malignant cells can be specifically earmarked for attack by a synthetic “designator”, the powerful effector mechanisms of the immune response can be conscripted to treat cancer. To implement this strategy, we have been developing aptamer-derived molecular adaptors to invoke synthetic immune responses against cancer cells. Here we describe multi-valent aptamers that simultaneously bind target molecules on the surface of cancer cells and an activated complement protein, which would tag the target molecules and their associated cells as “foreign” and trigger multiple effector mechanisms. Increased deposition of the complement proteins on the surface of cancer cells via aptamer binding to membrane targets could induce the formation of the membrane attack complex or cytotoxic degranulation by phagocytes and natural killer cells, thereby causing irreversible destruction of the targeted cells. Specifically, we designed and constructed a bi-functional aptamer linking EGFR and C3b/iC3b, and used it in a cell-based assay to cause lysis of MDA-MB-231 and BT-20 breast cancer cells, with either human or mouse serum as the source of complement factors.

Comprehensive cancer genomics-based screening of new therapeutic targets and biomarkers for lung cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21031-e21031
Author(s):  
Yataro Daigo ◽  
Atsushi Takano ◽  
Yusuke Nakamura
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Therapeutic Target ◽  
Cancer Genomics ◽  
Cancer Biomarkers ◽  
Lung Cancer Cells ◽  
Lung Cancers ◽  
Lung Cancer Patients ◽  
Target Molecules

e21031 Background: Since the clinical outcome of advanced lung cancer patients is still poor after standard therapies, development of new anti-cancer drugs with minimum risk of adverse effects and cancer biomarkers for precision medicine is urgently required. Methods: We have been screening new therapeutic target molecules and molecular biomarkers for lung cancers as follows; i) To identify overexpressed genes in lung cancers by the gene expression profile analysis, ii) To verify the target genes for their scarce expression in normal tissues, iii) To validate the clinicopathologic importance of their protein expression by tissue microarray covering 263 lung cancers, and iv) To confirm their function for the growth and/or invasive ability of the lung cancer cells by siRNAs and gene transfection assays. Results: We identified dozens of candidate target molecules and selected a gene encoding protein with a GAP domain, LAPG1 (lung cancer-associated protein with Gap domain 1). Immunohistochemical analysis showed that LAPG1 expression was observed in 69.9% of lung cancers. Moreover positivity of LAPG1 expression was associated with poor prognosis of lung cancer patients. Knockdown of LAPG1 expression by siRNAs suppressed growth of lung cancer cells. Introduction of LAPG1 increased the invasive activity of mammalian cells, indicating that LAPG1 could be a prognostic biomarker and therapeutic target for lung cancers. Conclusions: Comprehensive cancer genomics-based screening could be useful for selection of new cancer biomarkers and molecular targets for developing small molecules, antibodies, nucleic acid drugs, and immunotherapies.

scholarly journals The Different Roads to Maintain Telomeres in Cancer Cells

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1525
Author(s):  
Rosario Perona
Keyword(s):  
Cancer Cells ◽  
A Cell ◽  
Protective Structures ◽  
Linear Chromosomes

Telomeres are the protective structures at the ends of linear chromosomes that progressively shorten each time that a cell divides, which is in part caused by the end-replication problem [...]

scholarly journals Identification of human complement Factor H as a ligand for L-selectin

1999 ◽  
Vol 341 (1) ◽  
pp. 61-69 ◽  
Author(s):  
Rajneesh MALHOTRA ◽  
Malcolm WARD ◽  
Robert B. SIM ◽  
Michael I. BIRD
Keyword(s):  
Protein Band ◽  
Exchange Chromatography ◽  
Factor H ◽  
Mouse Serum ◽  
Complement Factor ◽  
Human Complement ◽  
Complement Protein ◽  
Protein Database ◽  
Tnf Α ◽  
Plasma Factor

The selectin family of adhesion molecules (E-, P- and L-selectins) is involved in leukocyte recruitment to sites of inflammation and tissue damage. Recently it has been shown that L-selectin is involved not only in leukocyte tethering and rolling, but also plays an important role in leukocyte activation. For example, glycosylation-dependent cell-adhesion molecule 1 (GlyCAM-1), a known ligand for L-selectin, has been shown to enhance β2-integrin function. GlyCAM-1 is a secreted protein and is present in mouse serum at a concentration of approx. 1.5 μg/ml. There is no obvious GlyCAM-1 homologue in man and, to date, L-selectin ligand(s) from human serum have not been characterized. Therefore we have used L-selectin affinity chromatography, followed by ion-exchange chromatography, to isolate specific ligand(s) for L-selectin. Using this procedure, we have isolated three major glycoproteins of apparent molecular masses 170 kDa, 70 kDa and 50 kDa. The 170 kDa protein band was digested with trypsin and peptides were analysed by delayed extraction matrix-assisted laser desorption ionization MS and protein database searching. The 170 kDa protein was identified as the human complement protein Factor H. Human Factor H, isolated by a different method, was shown to bind specifically to L-selectin in the presence of CaCl2, and binding was inhibited by anti-L-selectin antibodies, fucoidan and lipopolysaccharide. Only a part of the purified Factor H preparation bound to immobilized L-selectin. The interaction of Factor H with leukocyte L-selectin was shown to induce the secretion of tumour necrosis factor-α (TNF-α). Pretreatment of Factor H with sialidase reduced both the binding of L-selectin to Factor H and the Factor H-induced L-selectin-mediated TNF-α secretion by leukocytes. Taken together, these results demonstrate that a post-translationally modified form of human plasma Factor H is a potential physiological ligand for L-selectin.

scholarly journals Establishment and Characterization of a Cell Line from Human Circulating Colon Cancer Cells

2015 ◽  
Vol 75 (5) ◽  
pp. 892-901 ◽  
Author(s):  
Laure Cayrefourcq ◽  
Thibault Mazard ◽  
Simon Joosse ◽  
Jérôme Solassol ◽  
Jeanne Ramos ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Colon Cancer Cells ◽  
A Cell

Interaction of C3b2–IgG complexes with complement proteins properdin, factor B and factor H: implications for amplification

2000 ◽  
Vol 349 (1) ◽  
pp. 217-223
Author(s):  
Emiliana JELEZAROVA ◽  
Anna VOGT ◽  
Hans U. LUTZ
Keyword(s):  
Present Report ◽  
Alternative Pathway ◽  
Fluid Phase ◽  
Factor H ◽  
Complement Protein ◽  
Factor B ◽  
Physiological Conditions ◽  
Amplification Loop ◽  
Target Molecules ◽  
Properdin Factor B

Nascent C3b can form ester bonds with various target molecules on the cell surface and in the fluid phase. Previously, we showed that C3b2-IgG complexes represent the major covalent product of C3 activation in serum [Lutz, Stammler, Jelezarova, Nater and Späth (1996) Blood 88, 184-193]. In the present report, binding of alternative pathway proteins to purified C3b2-IgG complexes was studied in the fluid phase by using biotinylated IgG for C3b2-IgG generation and avidin-coated plates to capture complexes. Up to seven moles of properdin ‘monomer’ bound per mole of C3b2-IgG at physiological conditions in the absence of any other complement protein. At low properdin/C3b2-IgG ratios bivalent binding was preferred. Neither factor H nor factor B affected properdin binding. On the other hand, properdin strongly stimulated factor B binding. Interactions of all three proteins with C3b2-IgG exhibited pH optima. An ionic strength optimum was most pronounced for properdin, while factor B binding was largely independent of the salt concentration. C3b2-IgG complexes were powerful precursors of the alternative pathway C3 convertase. In the presence of properdin, C3 convertase generated from C3b2-IgG cleaved about sevenfold more C3 than the enzyme generated on C3b. C3b2-IgG complexes could therefore maintain the amplification loop of complement longer than free C3b.

Abstract B45: A cell-based screening to identify nucleolar disruptors in cancer cells

2013 ◽  
Author(s):  
Lucia Morgado-Palacin ◽  
Susana Llanos ◽  
Carmen Blanco-Aparicio ◽  
Diego Megias ◽  
Joaquin Pastor ◽  
...  
Keyword(s):  
Cancer Cells ◽  
A Cell

scholarly journals Kurarinone from Sophora Flavescens Roots Triggers ATF4 Activation and Cytostatic Effects Through PERK Phosphorylation

Molecules ◽  
2019 ◽  
Vol 24 (17) ◽  
pp. 3110 ◽  
Author(s):  
Sakiko Nishikawa ◽  
Yuka Itoh ◽  
Muneshige Tokugawa ◽  
Yasumichi Inoue ◽  
Ken-ichi Nakashima ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Fate ◽  
Kinase Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Sophora Flavescens ◽  
Promoter Activation ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Stress Relieving ◽  
A Cell ◽  
Cellular Stresses

In response to cellular stresses, activating transcriptional factor 4 (ATF4) regulates the expression of both stress-relieving genes and apoptosis-inducing genes, eliciting cell fate determination. Since pharmacological activation of ATF4 exerts potent anti-tumor effects, modulators of ATF4 activation may have potential in cancer therapy. We herein attempted to identify small molecules that activate ATF4. A cell-based screening to monitor TRB3 promoter activation was performed using crude drugs used in traditional Japanese Kampo medicine. We found that an extract from Sophora flavescens roots exhibited potent TRB3 promoter activation. The activity-guided fractionation revealed that kurarinone was identified as the active ingredient. Intriguingly, ATF4 activation in response to kurarinone required PKR-like endoplasmic reticulum kinase (PERK). Moreover, kurarinone induced the cyclin-dependent kinase inhibitor p21 as well as cytostasis in cancer cells. Importantly, the cytostatic effect of kurarinone was reduced by pharmacological inhibition of PERK. These results indicate that kurarinone triggers ATF4 activation through PERK and exerts cytostatic effects on cancer cells. Taken together, our results suggest that modulation of the PERK-ATF4 pathway with kurarinone has potential as a cancer treatment.

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