TACR1

Gene Summary

Gene:TACR1; tachykinin receptor 1
Aliases: SPR, NK1R, NKIR, TAC1R
Location:2p12
Summary:This gene belongs to a gene family of tachykinin receptors. These tachykinin receptors are characterized by interactions with G proteins and contain seven hydrophobic transmembrane regions. This gene encodes the receptor for the tachykinin substance P, also referred to as neurokinin 1. The encoded protein is also involved in the mediation of phosphatidylinositol metabolism of substance P. [provided by RefSeq, Sep 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:substance-P receptor
Source:NCBIAccessed: 01 September, 2019

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TACR1 (cancer-related)

Liu X, Zhang L, Tong Y, et al.
MicroRNA-22 inhibits proliferation, invasion and metastasis of breast cancer cells through targeting truncated neurokinin-1 receptor and ERα.
Life Sci. 2019; 217:57-69 [PubMed] Related Publications
HEADING AIMS: This topic aims to clarify whether miR-22 directly targets and downregulates the expression of ERα and NK1R-Tr to inhibit the malignant behaviors of breast cancer cells.
MATERIALS AND METHODS: RT-PCR and Western Blotting were used to detect the expression profile of miR-22, NK1R-Tr and ERα. Luciferase reporter assay and CHIP experiment were conducted to investigate the regulation network between miR-22, NK1R-Tr and ERα. MCF-7-ERαI and MDA-MB-231-ERα cell lines were constructed to study the biological behaviors. The SP-NK1R-ERK1/2 signaling pathway was analyzed using Western Blotting. The subcutaneous and metastases tumor models were employed to study the effects of miR-22 on cell proliferation and metastasis of breast cancer cells in vivo.
KEY FINDINGS: MiR-22 expression level was significantly lower in breast cancerous tissues and cell lines than the adjacent normality, while that of NK1R-Tr increased. The ERα could positively regulate NK1R-Tr expression at DNA level. The descent degree of NK1R-Tr in MCF-7-ERαI cells was far less than that in wild MCF-7 cells, while the findings in MDA-MB-231-ERα cells was more apparent than wild MDA-MB-231 cells. The malignant phenotype was decreased in miR-22 overexpressing cells compared with the wild type. The peak of ERK1/2 phosphorylation was delayed and weakened in miR-22 overexpressing MCF-7 cells, which was agreed with the findings using NK1R-Tr antagonist. The size and number of metastatic tumors declined compared to the controls.
SIGNIFICANCE: MiR-22 downregulated the expression of NK1R-Tr and ERα to delay and weaken phosphorylation of ERK1/2 to inhibit proliferation and metastasis of breast cancer cells.

Zhang L, Wang L, Dong D, et al.
MiR-34b/c-5p and the neurokinin-1 receptor regulate breast cancer cell proliferation and apoptosis.
Cell Prolif. 2019; 52(1):e12527 [PubMed] Related Publications
OBJECTIVES: MiR-34 is a tumour suppressor in breast cancer. Neurokinin-1 receptor (NK1R), which is the predicted target of the miR-34 family, is overexpressed in many cancers. This study investigated the correlation and clinical significance of miR-34 and NK1R in breast cancer.
MATERIALS AND METHODS: Western blotting, quantitative reverse transcription-PCR (qRT-PCR) and luciferase assays were conducted to analyse the regulation of NK1R by miR-34 in MDA-MB-231, MCF-7, T47D, SK-BR-3 and HEK-293 T cells. MiR-34b/c-5p, full-length NK1R (NK1R-FL) and truncated NK1R (NK1R-Tr) expression in fifty patients were quantified by qRT-PCR and correlated with their clinicopathological parameters. CCK-8 assays, colony formation assays and flow cytometry were used to measure cell proliferation and apoptosis in MDA-MB-231 and MCF-7 cells transfected with miR-34b/c-5p or NK1R-siRNA and before treatment with or without Substance P (SP), an endogenous peptide agonists of NK1R. The effect of NK1R antagonist aprepitant was also investigated. In vivo xenograft models were used to further verify the regulation of NK1R by miR-34b/c-5p.
RESULTS: Expression levels of miR-34b/c-5p and NK1R-Tr, but not NK1R-FL, were associated with enhanced malignant potential, such as tumour stage and Ki67 expression. The overexpression of miR-34b/c-5p or NK1R silencing potently suppressed cell proliferation and induced G2/M phase arrest and the apoptosis of MDA-MB-231 and MCF-7 cells. The NK1R antagonist aprepitant had similar effects. In vivo studies confirmed that miR-34b/c-5p overexpression or NK1R silencing reduced the tumorigenicity of breast cancer. In addition, SP rescued the effects of miR-34b/c-5p overexpression or NK1R silencing on cell proliferation and apoptosis in vitro and in vivo assays.
CONCLUSIONS: MiR-34b/c-5p and NK1R contribute to breast cancer cell proliferation and apoptosis and are potential targets for breast cancer therapeutics.

Zhang L, Chen Y, Liu N, et al.
Design, synthesis and anti leukemia cells proliferation activities of pyrimidylaminoquinoline derivatives as DOT1L inhibitors.
Bioorg Chem. 2018; 80:649-654 [PubMed] Related Publications
A series of novel pyrimidylaminoquinoline derivatives 8(a-i) and 9(a-i) containing amino side chain, and the bisaminoquinoline analogs 3(b-e) have been designed and synthesized by structural modifications on a lead DOT1L inhibitor, 3a. All the compounds have been evaluated for their DOT1L inhibitory activities. The results showed that most of the compounds have strong anti DOT1L activities. Compounds 3e, 8h and 9e are the most potential ones from each category with the IC

Huang C, Li Y, Guo Y, et al.
MMP1/PAR1/SP/NK1R paracrine loop modulates early perineural invasion of pancreatic cancer cells.
Theranostics. 2018; 8(11):3074-3086 [PubMed] Free Access to Full Article Related Publications
The molecular mechanism of perineural invasion (PNI) is unclear, and insufficient detection during early-stage PNI

Khajeh S, Tohidkia MR, Aghanejad A, et al.
Phage display selection of fully human antibody fragments to inhibit growth-promoting effects of glycine-extended gastrin 17 on human colorectal cancer cells.
Artif Cells Nanomed Biotechnol. 2018; 46(sup2):1082-1090 [PubMed] Related Publications
Glycine-extended gastrin 17 (G17-Gly), a dominant processing intermediate of gastrin gene, has been implicated in the development or maintenance of colorectal cancers (CRCs). Hence, neutralizing G17-Gly activity by antibody entities can provide a potential therapeutic strategy in the patients with CRCs. To this end, we isolated fully human antibody fragments from a phage antibody library through biopanning against different epitopes of G17-Gly in order to obtain the highest possible antibody diversity. ELISA screening and sequence analysis identified 2 scFvs and 4 V

Vanaja GR, Ramulu HG, Kalle AM
Overexpressed HDAC8 in cervical cancer cells shows functional redundancy of tubulin deacetylation with HDAC6.
Cell Commun Signal. 2018; 16(1):20 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Histone deacetylases (HDACs) are involved in epigenetic gene regulation via deacetylation of acetylated lysine residues of both histone and non-histone proteins. Among the 18 HDACs identified in humans, HDAC8, a class I HDAC, is best understood structurally and enzymatically. However, its precise subcellular location, function in normal cellular physiology, its protein partners and substrates still remain elusive.
METHODS: The subcellular localization of HDAC8 was studied using immunofluorescence and confocal imaging. The binding parterns were identified employing immunoprecipitation (IP) followed by MALDI-TOF analysis and confirmed using in-silico protein-protein interaction studies, HPLC-based in vitro deacetylation assay, intrinsic fluorescence spectrophotometric analysis, Circular dichroism (CD) and Surface Plasmon Resonance (SPR). Functional characterization of the binding was carried out using immunoblot and knockdown by siRNA. Using one way ANOVA statistical significance (n = 3) was determined.
RESULTS: Here, we show that HDAC8 and its phosphorylated form (pHDAC8) localized predominantly in the cytoplasm in cancerous, HeLa, and non-cancerous (normal), HEK293T, cells, although nucleolar localization was observed in HeLa cells. The study identified Alpha tubulin as a novel interacting partner of HDAC8. Further, the results indicated binding and deacetylation of tubulin at ac-lys40 by HDAC8. Knockdown of HDAC8 by siRNA, inhibition of HDAC8 and/or HDAC6 by PCI-34051 and tubastatin respectively, cell-migration, cell morphology and cell cycle analysis clearly explained HDAC8 as tubulin deacetylase in HeLa cells and HDAC6 in HEK 293 T cells.
CONCLUSIONS: HDAC8 shows functional redundancy with HDAC6 when overexpressed in cervical cancer cells, HeLa, and deacetylaes ac-lys40 of alpha tubulin leading to cervical cancer proliferation and progression.

Bayati S, Razani E, Bashash D, et al.
Antileukemic effects of neurokinin-1 receptor inhibition on hematologic malignant cells: a novel therapeutic potential for aprepitant.
Anticancer Drugs. 2018; 29(3):243-252 [PubMed] Related Publications
Genetic and laboratory studies have remodeled the conventional understanding of cancer pathogenesis by identifying different molecular alterations. Intrigued by the contribution of neurokinin-1 receptor (NK1R) network in cancer pathogenesis, we investigated the antileukemic effects of aprepitant, a nonpeptide antagonist of NK1R, in a panel of hematological cell lines. In this study, we found that aprepitant decreased the survival of all the tested cells; however, as compared with NB4, viability of the other cell lines was inhibited at higher concentrations. By increasing both p21 and p73 along with suppressing c-Myc and hTERT, aprepitant probably disordered cell distribution in the cell cycle, decreased DNA replication rate, and, thereby, impeded the proliferative capability of NB4 cells. Moreover, exposing cells to this agent led to activation of the caspase-3-dependent apoptotic pathway through altering the expression of apoptosis-related genes. Noteworthy, aprepitant also sensitized NB4 cells to the cytotoxic effects of arsenic trioxide and vincristine. Overall, it seems that pharmaceutical targeting of NK1R using aprepitant, either as a single agent or in combination, possesses novel promising potential for leukemia treatment strategies.

Pohl A, Kappler R, Mühling J, et al.
Expression of Truncated Neurokinin-1 Receptor in Childhood Neuroblastoma is Independent of Tumor Biology and Stage.
Anticancer Res. 2017; 37(11):6079-6085 [PubMed] Related Publications
BACKGROUND: Neuroblastoma is an embryonal malignancy arising from the aberrant growth of neural crest progenitor cells of the sympathetic nervous system. The tachykinin receptor 1 (TACR1) - substance P complex is associated with tumoral angiogenesis and cell proliferation in a variety of cancer types. Inhibition of TACR1 was recently described to impede growth of NB cell lines. However, the relevance of TACR1 in clinical settings is unknown.
PATIENTS AND METHODS: We investigated gene expression levels of full-length and truncated TACR1 in 59 neuroblastomas and correlated these data with the patients' clinical parameters such as outcome, metastasis, International Neuroblastoma Staging System (INSS) status, MYCN proto-oncogene, bHLH transcription factor (MYCN) status, gender and age.
RESULTS: Our results indicated that TACR1 is ubiquitously expressed in neuroblastoma but expression levels are independent of clinical parameters.
CONCLUSION: Our data suggest that TACR1 might serve as a potent anticancer target in a large variety of patients with neuroblastoma, independent of tumor biology and clinical stage.

Zhuge W, Chen R, Vladimir K, et al.
Costunolide specifically binds and inhibits thioredoxin reductase 1 to induce apoptosis in colon cancer.
Cancer Lett. 2018; 412:46-58 [PubMed] Related Publications
Colon cancer is one of the leading causes of cancer-related deaths. A natural sesquiterpene lactone, costunolide (CTD), showed inhibition of cancer development. However, the underlying mechanisms are not known. Here, we have examined the therapeutic activity and novel mechanisms of the anti-cancer activities of CTD in colon cancer cells. Using SPR analysis and enzyme activity assay on recombinant TrxR1 protein, our results show that CTD directly binds and inhibits the activity of TrxR1, which caused enhanced generation of ROS and led to ROS-dependent endoplasmic reticulum stress and cell apoptosis in colon cancer cells. Overexpression of TrxR1 in HCT116 cells reversed CTD-induced cell apoptosis and ROS increase. CTD treatment of mice implanted with colon cancer cells showed tumor growth inhibition and reduced TrxR1 activity and ROS level. In addition, it was observed that TrxR1 was significantly up-regulated in existing colon cancer gene database and clinically obtained colon cancer tissues. Our studies have uncovered the mechanism underlying the biological activity of CTD in colon cancer and suggest that targeting TrxR1 may prove to be beneficial as a treatment option.

Xiang D, Han J, Yao T, et al.
Editor's Highlight: Structure-Based Investigation on the Binding and Activation of Typical Pesticides With Thyroid Receptor.
Toxicol Sci. 2017; 160(2):205-216 [PubMed] Related Publications
A broad range of pesticides have been reported to interfere with the normal function of the thyroid endocrine system. However, the precise mechanism(s) of action has not yet been thoroughly elucidated. In this study, 21 pesticides were assessed for their binding interactions and the potential to disrupt thyroid homeostasis. In the GH3 luciferase reporter gene assays, 5 of the pesticides tested had agonistic effects in the order of procymidone > imidacloprid > mancozeb > fluroxypyr > atrazine. 11 pesticides inhibited luciferase activity of T3 to varying degrees, demonstrating their antagonistic activity. And there are 4 pesticides showed mixed effects when treated with different concentrations. Surface plasmon resonance (SPR) biosensor technique was used to directly measure the binding interactions of these pesticides to the human thyroid hormone receptor (hTR). 13 pesticides were observed to bind directly with TR, with a KD ranging from 4.80E-08 M to 9.44E-07 M. The association and disassociation of the hTR/pesticide complex revealed 2 distinctive binding modes between the agonists and antagonists. At the same time, a different binding mode was displayed by the pesticides showed mix agonist and antagonist activity. In addition, the molecular docking simulation analyses indicated that the interaction energy calculated by CDOCKER for the agonists and antagonists correlated well with the KD values measured by the surface plasmon resonance assay. These results help to explain the differences of the TR activities of these tested pesticides.

Itcho K, Oki K, Kobuke K, et al.
Aberrant G protein-receptor expression is associated with DNA methylation in aldosterone-producing adenoma.
Mol Cell Endocrinol. 2018; 461:100-104 [PubMed] Related Publications
This study aimed to evaluate the methylation levels of G protein-coupled receptor (GPCR) related genes and the effects of methylation on mRNA expression levels in aldosterone-producing adenoma (APA). DNA methylation array and transcriptome analysis were applied in non-functioning adrenocortical adenoma (NFA) and APA. We investigated 192 GPCR-related genes and found hypo-methylation in the promoter region of 66 of these genes in APA. An integration study between microarray and methylation analysis revealed that HTR4, MC2R, TACR1, GRM3, and PTGER1 showed hypo-methylation and up-regulation of mRNA in APA. qPCR analysis showed that HTR4 and PTGER1 expression was 9.3-fold and 6.6-fold higher in APAs than in NFAs, respectively, whereas expression of the other genes was not different between the groups. Methylation of HTR4 and PTGER1 at positions -229 and -666 from the transcription start site, respectively, showed a significant inverse correlation with their mRNA levels. Methylation levels were not associated with KCNJ5 or ATP1A1 mutations in human adrenal samples. We demonstrated an increased incidence of CpG island demethylation of GPCR-related gene in APA. The expression of two receptors, HTR4 and PTGER1, showed a strong association with DNA methylation.

Jiang W, Cheng Y, Zhao N, et al.
Sulfated polysaccharide of Sepiella Maindroni ink inhibits the migration, invasion and matrix metalloproteinase-2 expression through suppressing EGFR-mediated p38/MAPK and PI3K/Akt/mTOR signaling pathways in SKOV-3 cells.
Int J Biol Macromol. 2018; 107(Pt A):349-362 [PubMed] Related Publications
Previous studies demonstrated that SIP-SII, a sulfated derivative of SIP that is isolated from the ink of Sepiella maindroni, showed significant inhibition of tumor growth and metastasis. In this study, the effects of SIP-SII on the migration, invasion and molecular mechanism in ovarian cancer cell line, SKOV-3 cells, were investigated. The flow cytometry, confocal microscope observation, western blot and RT-PCR results indicated that SIP-SII located on cell membrane and inhibited the expression and activation of epidermal growth factor receptor (EGFR). Moreover, the binding capacity of SIP-SII with EGFR was confirmed by surface plasmon resonance (SPR) analysis and co-localization of EGFR and SIP-SII. Accordingly, SIP-SII was proved to attenuate the EGF-induced EGFR phosphorylation and migration by western blot and wound healing assay, respectively. Additionally, SIP-SII inhibited p38/MAPK and PI3K/Akt/mTOR signaling pathways in SKOV-3 cells significantly. What is more, SIP-SII showed amplified inhibitory activity on migration, invasion, and MMP-2 expression in combination with p38-specific inhibitor, PI3K-specific inhibitor or mTOR-specific inhibitor in SKOV-3 cells. Therefore, the mechanism that SIP-SII suppressed EGFR-mediated p38/MAPK and PI3K/Akt/mTOR signaling pathways to inhibit migration and invasion of SKOV-3 cells was demonstrated. These findings suggested that SIP-SII might be used as a potential inhibitor against tumor metastasis.

Lin D, Guo Y, Li Y, et al.
Bioinformatic analysis reveals potential properties of human Claudin-6 regulation and functions.
Oncol Rep. 2017; 38(2):875-885 [PubMed] Free Access to Full Article Related Publications
Claudin-6 (CLDN6) is an integral component of the tight junction proteins in polarized epithelial and endothelial cells and plays a crucial role in maintaining cell integrity. Deregulation of CLDN6 expression and distribution in tumor tissues have been widely documented and correlated with cancer progression and metastasis. However, a complete mechanistic understanding of CLDN6 regulation and function remains to be studied. Herein, we show new potential properties of CLDN6 regulation and functions from bioinformatics analysis. Using numerous algorithms to characterize the CLDN6 gene promoter elements and the CLDN6 protein structure, physio-chemical and localization properties, and its evolutionary relationships. CLDN6 is regulated by a diverse set of transcription factors (SP1, SPR, AML-1a, CdxA, CRE-BP and CREB) and associated with the levels of methylation of CpG islands in promoters. The structural properties of CLDN6 indicate that it promotes cancer cell behavior via the ASK1-p38/JNK MAPK secretory signaling pathway. In conclusion, this information from bioinformatics analysis will help future attempts to better understand CLDN6 regulation and functions.

Sokolowska-Wedzina A, Chodaczek G, Chudzian J, et al.
High-Affinity Internalizing Human scFv-Fc Antibody for Targeting FGFR1-Overexpressing Lung Cancer.
Mol Cancer Res. 2017; 15(8):1040-1050 [PubMed] Related Publications
Targeted delivery of anticancer drugs using antibodies specific for tumor-associated antigens represents one of the most important approaches in current immuno-oncology research. Fibroblast growth factor receptor 1 (FGFR1) has been demonstrated to be a high-frequency targetable oncogene specific for smoking-associated lung cancers, present in over 20% of lung squamous cell carcinoma cases. This report describes the generation of a potent, fully human antibody fragment in scFv-Fc format efficiently targeting FGFR1. Antibody phage display was used to select high-affinity scFv antibody fragments against the extracellular domain of FGFR1(IIIc). Enzyme immunoassay (ELISA) and surface plasmon resonance (SPR) analysis were used for antibody screening and characterization. The best binder (named D2) was cloned to diabody and Fc fusion formats. All D2 antibodies demonstrated high affinity for FGFR1 with dissociation constants of 18 nmol/L (scFvD2), 0.82 nmol/L (scFvD2 diabody), and 0.59 nmol/L (scFvD2-Fc). scFvD2 was found to be exquisitely selective for FGFR1 versus other FGFR family members and bound FGFR1 even in the presence of its natural ligand FGF2, as shown by competitive analysis. Confocal microscopy revealed that scFvD2-Fc was specifically and rapidly internalized by a panel of cell lines overexpressing FGFR1. Finally, it was demonstrated that scFvD2-Fc mediated specific delivery of a cytotoxic payload into lung cancer cells harboring oncogenic

Chen X, Xu H, Wu N, et al.
Interaction between granulin A and enolase 1 attenuates the migration and invasion of human hepatoma cells.
Oncotarget. 2017; 8(18):30305-30316 [PubMed] Free Access to Full Article Related Publications
Granulin A (GRN A), a peptide with a molecular 6 kDa, is derived from proteolysis of progranulin (PGRN). Previous study in our laboratory has shown that GRN A is able to inhibit cancer cell growth significantly. In the present study, we confirmed that GRN A can bind to α-enolase (ENO1) specifically as analyzed using Pull-down/MS approaches. The interaction of GRN A with ENO1 was further confirmed by Western blotting and Surface plasmon resonance (SPR) analysis. Treatment of human HepG-2 cells with GRN A inhibited cancer cell growth as well as migration and invasion of cancer cells as analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazoliumbromide (MTT) and Scratch wound healing assay as well as Transwell experiments. Additionally, GRN A treatment results in augmentation of glucose uptake in cancer cells. Further study reveals that higher expression of ENO1 reversed the inhibitory effects of GRN A on migration and invasion of HepG-2 cells. The increase of glucose uptake, as well as the expression of apoptosis-related genes, is also reversed in cells overexpressing ENO1. The study provides solid evidence that there is the interaction between GRN A and ENO1 and the interaction is responsible for the effects of GRN A on glucose uptake as well as cancer cell migration and invasion.

Zhang YX, Li XF, Yuan GQ, et al.
β-Arrestin 1 has an essential role in neurokinin-1 receptor-mediated glioblastoma cell proliferation and G
J Biol Chem. 2017; 292(21):8933-8947 [PubMed] Free Access to Full Article Related Publications
Glioblastoma is the most common malignant brain tumor and has a poor prognosis. Tachykinin receptor neurokinin-1 (NK1R) is a promising target in glioblastoma therapy because of its overexpression in human glioblastoma. NK1R agonists promote glioblastoma cell growth, whereas NK1R antagonists efficiently inhibit cell growth both

Duan J, Xiaokaiti Y, Fan S, et al.
Direct interaction between caffeic acid phenethyl ester and human neutrophil elastase inhibits the growth and migration of PANC-1 cells.
Oncol Rep. 2017; 37(5):3019-3025 [PubMed] Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant tumors of the digestive system, but the mechanisms of its development and progression are unclear. Inflammation is thought to be fundamental to pancreatic cancer development and caffeic acid phenethyl ester (CAPE) is an active component of honey bee resin or propolis with anti-inflammatory and anticancer activities. We investigated the inhibitory effects of CAPE on cell growth and migration induced by human neutrophil elastase (HNE) and report that HNE induced cancer cell migration at low doses and growth at higher doses. In contrast, lower CAPE doses inhibited migration and higher doses of CAPE inhibited the growth induced by HNE. HNE activity was significantly inhibited by CAPE (7.5-120 µM). Using quantitative real-time PCR and western blotting, we observed that CAPE (18-60 µM) did not affect transcription and translation of α1-antitrypsin (α1-AT), an endogenous HNE inhibitor. However, in an in silico drug target docking model, we found that CAPE directly bound to the binding pocket of HNE (25.66 kcal/mol) according to CDOCKER, and the residue of the catalytic site stabilized the interaction between CAPE and HNE as evidenced by molecular dynamic simulation. Response unit (RU) values of surface plasmon resonance (SPR) significantly increased with incremental CAPE doses (7.5-120 µM), indicating that CAPE could directly bind to HNE in a concentration-dependent manner. Thus, CAPE is an effective inhibitor of HNE via direct interaction whereby it inhibits the migration and growth of PANC-1 cells in a dose-dependent manner.

Chehboun S, Labrecque-Carbonneau J, Pasquin S, et al.
Epstein-Barr virus-induced gene 3 (EBI3) can mediate IL-6
J Biol Chem. 2017; 292(16):6644-6656 [PubMed] Free Access to Full Article Related Publications
Epstein-Barr virus-induced gene 3 (EBI3) is a subunit of the composite cytokines IL-27 and IL-35. Both have beneficial functions or effects in models of infectious and autoimmune diseases. This suggests that administration of EBI3 could be therapeutically useful by binding free p28 and p35 to generate IL-27 and IL-35. IL-27- and IL-35-independent functions of EBI3 could compromise its therapeutic uses. We therefore assessed the effects of EBI3 on cytokine receptor-expressing cells. We observed that EBI3 activates STAT3 and induces the proliferation of the IL-6-dependent B9 mouse plasmacytoma cell line. Analyses using blocking mAbs and Ba/F3 transfectants expressing gp130 indicate that EBI3 activity was linked to its capacity to mediate IL-6

Capek I
Polymer decorated gold nanoparticles in nanomedicine conjugates.
Adv Colloid Interface Sci. 2017; 249:386-399 [PubMed] Related Publications
Noble metal, especially gold nanoparticles and their conjugates with biopolymers have immense potential for disease diagnosis and therapy on account of their surface plasmon resonance (SPR) enhanced light scattering and absorption. Conjugation of noble metal nanoparticles to ligands specifically targeted to biomarkers on diseased cells allows molecular-specific imaging and detection of disease. The development of smart gold nanoparticles (AuNPs) that can deliver therapeutics at a sustained rate directly to cancer cells may provide better efficacy and lower toxicity for treating cancer tumors. We highlight some of the promising classes of targeting systems that are under development for the delivery of gold nanoparticles. Nanoparticles designed for biomedical applications are often coated with polymers containing reactive functional groups to conjugate targeting ligands, cell receptors or drugs. Using targeted nanoparticles to deliver chemotherapeutic agents in cancer therapy offers many advantages to improve drug/gene delivery and to overcome many problems associated with conventional radiotherapy and chemotherapy. The targeted nanoparticles were found to be effective in killing cancer cells which were studied using various anticancer assays. Cell morphological analysis shows the changes occurred in cancer cells during the treatment with AuNPs. The results determine the influence of particle size and concentration of AuNPs on their absorption, accumulation, and cytotoxicity in model normal and cancer cells. As the mean particle diameter of the AuNPs decreased, their rate of absorption by the intestinal epithelium cells increased. These results provide important insights into the relationship between the dimensions of AuNPs and their gastrointestinal uptake and potential cytotoxicity. Furthermore gold nanoparticles efficiently convert the absorbed light into localized heat, which can be exploited for the selective laser photothermal therapy of cancer. We also review the emerging technologies for the fabrication of targeted gold colloids as imagining agents.

Henssen AG, Odersky A, Szymansky A, et al.
Targeting tachykinin receptors in neuroblastoma.
Oncotarget. 2017; 8(1):430-443 [PubMed] Free Access to Full Article Related Publications
Neuroblastoma is the most common extracranial tumor in children. Despite aggressive multimodal treatment, high-risk neuroblastoma remains a clinical challenge with survival rates below 50%. Adding targeted drugs to first-line therapy regimens is a promising approach to improve survival in these patients. TACR1 activation by substance P has been reported to be mitogenic in cancer cell lines. Tachykinin receptor (TACR1) antagonists are approved for clinical use as an antiemetic remedy since 2003. Tachykinin receptor inhibition has recently been shown to effectively reduce growth of several tumor types. Here, we report that neuroblastoma cell lines express TACR1, and that targeting TACR1 activity significantly reduced cell viability and induced apoptosis in neuroblastoma cell lines. Gene expression profiling revealed that TACR1 inhibition repressed E2F2 and induced TP53 signaling. Treating mice harboring established neuroblastoma xenograft tumors with Aprepitant also significantly reduced tumor burden. Thus, we provide evidence that the targeted inhibition of tachykinin receptor signaling shows therapeutic efficacy in preclinical models for high-risk neuroblastoma.

Banerjee J, Pradhan R, Gupta A, et al.
CDK4 in lung, and head and neck cancers in old age: evaluation as a biomarker.
Clin Transl Oncol. 2017; 19(5):571-578 [PubMed] Related Publications
BACKGROUND: Cyclin dependent kinases (CDK) are key factors in promoting the initiation and development of tumors. These kinases are important for maintenance of mitochondrial biogenesis and imbalance in their expression in old age may lead to the oxidative stress. Lung cancer (LC), and head and neck squamous cell carcinoma (HNSCC) are two very prominent cancers in older Indians. Both the cancers are showing increasing trend in older population. The present study assessed serum concentration of one of the kinases; CDK4 in older LC and HNSCC patients.
METHODS: The study included 100 subjects each of LC and HNSCC; and older subjects without cancer or any major health problems as controls. Serum CDK4 concentration was estimated using real-time label-free Surface plasmon resonance (SPR) and was verified by western blot.
RESULTS: Significant elevation in serum CDK4 was observed in cases with LC and HNSCC compared to controls. HNSCC patients with higher CDK4 expression had distinctly shorter survival than patients with comparatively lower CDK4 expression. No such difference was observed in LC patients. The germ line mutation study of this gene in Exon-2 was performed and none was observed among cases and controls.
CONCLUSION: It can be concluded that older patients with HNSCC and lung cancer have raised serums CDK4 levels, which has the potential to emerge as a biomarker in clinical practice.

Bayati S, Bashash D, Ahmadian S, et al.
Inhibition of tachykinin NK
Eur J Pharmacol. 2016; 791:274-283 [PubMed] Related Publications
Increasing number of genetic and cancer biology studies indicated a prominent role for tachykinin NK

González-Santana A, Marrero-Hernández S, Dorta I, et al.
Altered expression of the tachykinins substance P/neurokinin A/hemokinin-1 and their preferred neurokinin 1/neurokinin 2 receptors in uterine leiomyomata.
Fertil Steril. 2016; 106(6):1521-1529 [PubMed] Related Publications
OBJECTIVE: To study the expression levels of tachykinins and tachykinin receptors in uterine leiomyomas and matched myometrium.
DESIGN: Laboratory study.
SETTING: University research laboratories and academic hospital.
PATIENT(S): Women undergoing hysterectomy for symptomatic leiomyomas.
INTERVENTION(S): Quantitative polymerase chain reaction, immunohistochemistry and Western blot.
MAIN OUTCOME MEASURE(S): Expression and tissue immunostaining of substance P, neurokinin A, hemokinin-1, neurokinin 1 receptor full-length (NK1R-Fl) and truncated (NK1R-Tr) isoforms, and neurokinin 2 receptor (NK2R) in paired samples of leiomyoma and adjacent normal myometrium.
RESULT(S): TAC1 messenger RNA (mRNA) was significantly up-regulated in leiomyomas, whereas intense immunoreaction for the three peptides was particularly abundant in connective tissue cells. Differential regulation of TACR1 mRNA was observed, and at the protein level there was a significant increased expression of NK1R short isoform (NK1R-Tr). TACR2 mRNA was significantly up-regulated in leiomyomas, although levels of NK2R protein were similar in normal and tumor cells.
CONCLUSION(S): These and our previous data demonstrate that the whole tachykinin system is differentially regulated in leiomyomas. The increased expression of NK1R-Tr might stimulate leiomyoma growth in a similar way to that observed in other steroid-dependent tumors.

Kumar R, Singh AK, Kumar M, et al.
Serum 5-LOX: a progressive protein marker for breast cancer and new approach for therapeutic target.
Carcinogenesis. 2016; 37(9):912-7 [PubMed] Related Publications
Lipoxygenase (LOX) pathway has emerged to have a role in carcinogenesis. There is an evidence that both 12-LOX and 5-LOX have procarcinogenic role. We have previously reported the elevated level of serum 12-LOX in breast cancer patients. This study evaluated the serum level of 5-LOX in breast cancer patients and its in vitro inhibition assessment with peptide inhibitor YWCS. The level of 5-LOX was determined by surface plasmon resonance (SPR). The peptide inhibitor of 5-LOX was designed by molecular modeling and kinetic assay was performed by spectrophotometry. The siRNA mediated 5-LOX gene silencing was performed to investigate the effect on proliferation of MDA-MB-231, breast cancer cell line. The serum 5-LOX level in breast cancer (5.69±1.97ng/µl) was almost 2-fold elevated compared to control (3.53±1.0ng/µl) (P < 0.0001). The peptide YWCS had shown competitive inhibitory effects with IC50, 2.2 µM and dissociation constant (K D), 4.92×10(-8) M. The siRNA mediated knockdown of 5-LOX, resulted in the decreased gene expression for 5-LOX and increased cell death in MDA-MB-231 cell line and thereby play a key role in reducing tumor proliferation. Thus, it can be concluded that 5-LOX is one of the potential serum protein marker for breast cancer and a promising therapeutic target for the same.

Kurita GP, Ekholm O, Kaasa S, et al.
Genetic variation and cognitive dysfunction in opioid-treated patients with cancer.
Brain Behav. 2016; 6(7):e00471 [PubMed] Free Access to Full Article Related Publications
BACKGROUND AND PURPOSE: The effects of single-nucleotide polymorphisms (SNPs) on the cognitive function of opioid-treated patients with cancer until now have not been explored, but they could potentially be related to poor functioning. This study aimed at identifying associations between SNPs of candidate genes, high opioid dose, and cognitive dysfunction.
METHODS: Cross-sectional multicenter study (European Pharmacogenetic Opioid Study, 2005-2008); 1586 patients; 113 SNPs from 41 genes.
INCLUSION CRITERIA: cancer, age ≥18 year, opioid treatment, and available genetic data. Cognitive assessment by Mini-Mental State Examination (MMSE).
ANALYSES: SNPs were rejected if violation of Hardy-Weinberg equilibrium (P < 0.0005), or minor allele frequency <5%; patients were randomly divided into discovery sample (2/3 for screening) and validation sample (1/3 for confirmatory test); false discovery rate of 10% for determining associations (Benjamini-Hochberg method). Co-dominant, dominant, and recessive models were analyzed by Kruskal-Wallis and Mann-Whitney tests.
RESULTS: In the co-dominant model significant associations (P < 0.05) between MMSE scores and SNPs in the HTR3E,TACR1, and IL6 were observed in the discovery sample, but the replication in the validation sample did not confirm it. Associations between MMSE scores among patients receiving ≥400 mg morphine equivalent dose/day and SNPs in TNFRSF1B,TLR5,HTR2A, and ADRA2A were observed, but they could not be confirmed in the validation sample. After correction for multiple testing, no SNPs were significant in the discovery sample. Dominant and recessive models also did not confirm significant associations.
CONCLUSIONS: The findings did not support influence of those SNPs analyzed to explain cognitive dysfunction in opioid-treated patients with cancer.

Zheng J, Son DJ, Gu SM, et al.
Piperlongumine inhibits lung tumor growth via inhibition of nuclear factor kappa B signaling pathway.
Sci Rep. 2016; 6:26357 [PubMed] Free Access to Full Article Related Publications
Piperlongumine has anti-cancer activity in numerous cancer cell lines via various signaling pathways. But there has been no study regarding the mechanisms of PL on the lung cancer yet. Thus, we evaluated the anti-cancer effects and possible mechanisms of PL on non-small cell lung cancer (NSCLC) cells in vivo and in vitro. Our findings showed that PL induced apoptotic cell death and suppressed the DNA binding activity of NF-κB in a concentration dependent manner (0-15 μM) in NSCLC cells. Docking model and pull down assay showed that PL directly binds to the DNA binding site of nuclear factor-κB (NF-κB) p50 subunit, and surface plasmon resonance (SPR) analysis showed that PL binds to p50 concentration-dependently. Moreover, co-treatment of PL with NF-κB inhibitor phenylarsine oxide (0.1 μM) or p50 siRNA (100 nM) augmented PL-induced inhibitory effect on cell growth and activation of Fas and DR4. Notably, co-treatment of PL with p50 mutant plasmid (C62S) partially abolished PL-induced cell growth inhibition and decreased the enhanced expression of Fas and DR4. In xenograft mice model, PL (2.5-5 mg/kg) suppressed tumor growth of NSCLC dose-dependently. Therefore, these results indicated that PL could inhibit lung cancer cell growth via inhibition of NF-κB signaling pathway in vitro and in vivo.

Cho JG, Park S, Lim CH, et al.
ZNF224, Krüppel like zinc finger protein, induces cell growth and apoptosis-resistance by down-regulation of p21 and p53 via miR-663a.
Oncotarget. 2016; 7(21):31177-90 [PubMed] Free Access to Full Article Related Publications
ZNF224 is a Krüppel-associated box-containing zinc-finger protein which represses gene transcription by interacting with various co-repressors. However, its consensus DNA sequences and target genes are not fully identified. In this study, we identified and characterized consensus DNA sequences containing 5'-CAGC-3' recognized by ZNF224 through ChIP-sequencing, which further confirmed by ELISA, SPR, qPCR, and luciferase activity assay. ZNF224 increased miR-663a transcription by binding to miR-663a promoter, which in turn binds to 3' UTR of p53 and p21 to decrease their expression. miR-663a antagonist abolished ZNF224-mediated suppression of p21 and p53, resulting in the enhanced apoptosis by CPT. The analyses using human breast ductal carcinoma tissues exhibited that the expression of ZNF224 and miR-663a was increased in cancer compared to non-cancer region. Consequently, ZNF224 increases cell survival and decreases apoptosis by decreasing the expression of p53 and p21 via miR-663a as a transcriptional activator. Taken together, we identified and characterized DNA binding element of ZNF224, and its target genes, miR-663a, which provides a novel insight in the down-regulation of p21 and p53 via miR-663a by ZNF224 in breast cancer.

Kundu M, Mahata B, Banerjee A, et al.
Ganglioside GM2 mediates migration of tumor cells by interacting with integrin and modulating the downstream signaling pathway.
Biochim Biophys Acta. 2016; 1863(7 Pt A):1472-89 [PubMed] Related Publications
The definitive role of ganglioside GM2 in mediating tumor-induced growth and progression is still unknown. Here we report a novel role of ganglioside GM2 in mediating tumor cell migration and uncovered its mechanism. Data shows differential expression levels of GM2-synthase as well as GM2 in different human cancer cells. siRNA mediated knockdown of GM2-synthase in CCF52, A549 and SK-RC-26B cells resulted in significant inhibition of tumor cell migration as well as invasion in vitro without affecting cellular proliferation. Over-expression of GM2-synthase in low-GM2 expressing SK-RC-45 cells resulted in a consequent increase in migration thus confirming the potential role GM2 and its downstream partners play in tumor cell migration and motility. Further, treatment of SK-RC-45 cells with exogenous GM2 resulted in a dramatic increase in migratory and invasive capacity with no change in proliferative capacity, thereby confirming the role of GM2 in tumorigenesis specifically by mediating tumor migration and invasion. Gene expression profiling of GM2-synthase silenced cells revealed altered expression of several genes involved in cell migration primarily those controlling the integrin mediated signaling. GM2-synthase knockdown resulted in decreased phosphorylation of FAK, Src as well as Erk, while over-expression and/or exogenous GM2 treatment caused increased FAK and Erk phosphorylation respectively. Again, GM2 mediated invasion and Erk phosphorylation is blocked in integrin knockdown SK-RC-45 cells, thus confirming that GM2 mediated migration and phosphorylation of Erk is integrin dependent. Finally, confocal microscopy suggested co-localization while co-immunoprecipitation and surface plasmon resonance (SPR) confirmed direct interaction of membrane bound ganglioside, GM2 with the integrin receptor.

Paugh SW, Coss DR, Bao J, et al.
MicroRNAs Form Triplexes with Double Stranded DNA at Sequence-Specific Binding Sites; a Eukaryotic Mechanism via which microRNAs Could Directly Alter Gene Expression.
PLoS Comput Biol. 2016; 12(2):e1004744 [PubMed] Free Access to Full Article Related Publications
MicroRNAs are important regulators of gene expression, acting primarily by binding to sequence-specific locations on already transcribed messenger RNAs (mRNA) and typically down-regulating their stability or translation. Recent studies indicate that microRNAs may also play a role in up-regulating mRNA transcription levels, although a definitive mechanism has not been established. Double-helical DNA is capable of forming triple-helical structures through Hoogsteen and reverse Hoogsteen interactions in the major groove of the duplex, and we show physical evidence (i.e., NMR, FRET, SPR) that purine or pyrimidine-rich microRNAs of appropriate length and sequence form triple-helical structures with purine-rich sequences of duplex DNA, and identify microRNA sequences that favor triplex formation. We developed an algorithm (Trident) to search genome-wide for potential triplex-forming sites and show that several mammalian and non-mammalian genomes are enriched for strong microRNA triplex binding sites. We show that those genes containing sequences favoring microRNA triplex formation are markedly enriched (3.3 fold, p<2.2 × 10(-16)) for genes whose expression is positively correlated with expression of microRNAs targeting triplex binding sequences. This work has thus revealed a new mechanism by which microRNAs could interact with gene promoter regions to modify gene transcription.

Aykul S, Martinez-Hackert E
New Ligand Binding Function of Human Cerberus and Role of Proteolytic Processing in Regulating Ligand-Receptor Interactions and Antagonist Activity.
J Mol Biol. 2016; 428(3):590-602 [PubMed] Related Publications
Cerberus is a key regulator of vertebrate embryogenesis. Its biological function has been studied extensively in frog and mouse embryos. Its ability to bind and antagonize the transforming growth factor-β (TGF-β) family ligand Nodal is well established. Strikingly, the molecular function of Cerberus remains poorly understood. The underlying reason is that Cerberus is a complex, multifunctional protein: It binds and inhibits multiple TGF-β family ligands, it may bind and inhibit some Wnt family members, and two different forms with distinct activities have been described. In addition, sequence homology between frog and mammalian Cerberus is low, suggesting that previous studies, which analyzed frog Cerberus function, may not accurately describe the function of mammalian Cerberus. We therefore undertook to determine the molecular activities of human Cerberus in TGF-β family signaling. Using purified proteins, surface plasmon resonance, and reporter gene assays, we discovered that human Cerberus bound and inhibited the TGF-β family ligands Activin B, BMP-6, and BMP-7, but not the frog Cerberus ligand BMP-2. Notably, full-length Cerberus successfully blocked ligand binding to type II receptors, but the short form was less effective. In addition, full-length Cerberus suppressed breast cancer cell migration but the short form did not. Thus, our findings expand the roles of Cerberus as TGF-β family signaling inhibitor, provide a molecular rationale for the function of the N-terminal region, and support the idea that Cerberus could have regulatory activities beyond direct inhibition of TGF-β family signaling.

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