scholarly journals 1,4-dihydroxy Quininib Attenuates Growth of Colorectal Cancer Cells and Xenografts and Regulates the TIE-2 Signaling Pathway in Patient Tumours

2018 ◽  
Author(s):  
Clare T Butler ◽  
Susan Kennedy ◽  
Amy Buckley ◽  
Ronan Doyle ◽  
Emer Conroy ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Ex Vivo ◽  
Cancer Cell Line ◽  
Developed Countries ◽  
Colorectal Cancer Cell Line ◽  
Colorectal Tumour ◽  
Calpain 2 ◽  
Tumour Xenografts

Colorectal cancer (CRC) is the second leading cause of cancer associated deaths in developed countries. Cancer progression and metastatic spread is reliant on new blood vasculature, or angiogenesis. Tumour-related angiogenesis is regulated by pro- and anti-angiogenic factors secreted from malignant tissue in a stepwise process. Previously we structurally modified the small anti-angiogenic molecule quininib and discovered a more potent anti-angiogenic compound 1, 4 dihydroxy quininib (Q8), an antagonist of cysteinyl leukotriene receptor-1 with VEGF-independent bioactivity. Here, Q8, quininib (Q1) and five structural analogues were assayed for anti-tumorigenic effects in pre-clinical cancer models. Q8 reduced clone formation of the human colorectal cancer cell line HT29-Luc2. Gene silencing of CysLT1 in HT29-Luc2 cells significantly reduced expression of calpain-2. In human ex vivo colorectal cancer tumour explants, Q8 significantly decreased the secretion of both TIE-2 and VCAM-1 expression. In vivo Q8 was well tolerated up to 50 mg/kg by Balb/C mice and significantly more effective at reducing tumour volume in colorectal tumour xenografts compared to the parent drug quininib. In tumour xenografts, Q8 significantly reduced expression of the angiogenic marker calpain-2 in. In summary, we propose Q8 may act on the TIE-2-Angiopoietin signalling pathway to significantly inhibit the process of tumour angiogenesis in colorectal cancer.

scholarly journals Genome-Wide Pattern of TCF7L2/TCF4 Chromatin Occupancy in Colorectal Cancer Cells

2008 ◽  
Vol 28 (8) ◽  
pp. 2732-2744 ◽  
Author(s):  
Pantelis Hatzis ◽  
Laurens G. van der Flier ◽  
Marc A. van Driel ◽  
Victor Guryev ◽  
Fiona Nielsen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Binding Sites ◽  
Motif Discovery ◽  
Target Genes ◽  
Expression Profiles ◽  
Cancer Cell Line ◽  
Colorectal Cancer Cell Line ◽  
Genome Wide

ABSTRACT Wnt signaling activates gene expression through the induced formation of complexes between DNA-binding T-cell factors (TCFs) and the transcriptional coactivator β-catenin. In colorectal cancer, activating Wnt pathway mutations transform epithelial cells through the inappropriate activation of a TCF7L2/TCF4 target gene program. Through a DNA array-based genome-wide analysis of TCF4 chromatin occupancy, we have identified 6,868 high-confidence TCF4-binding sites in the LS174T colorectal cancer cell line. Most TCF4-binding sites are located at large distances from transcription start sites, while target genes are frequently “decorated” by multiple binding sites. Motif discovery algorithms define the in vivo-occupied TCF4-binding site as evolutionarily conserved A-C/G-A/T-T-C-A-A-A-G motifs. The TCF4-binding regions significantly correlate with Wnt-responsive gene expression profiles derived from primary human adenomas and often behave as β-catenin/TCF4-dependent enhancers in transient reporter assays.

scholarly journals Development of a Potential Gallium-68-Labelled Radiotracer Based on DOTA-Curcumin for Colon-Rectal Carcinoma: From Synthesis to In Vivo Studies

Molecules ◽  
2019 ◽  
Vol 24 (3) ◽  
pp. 644 ◽  
Author(s):  
Giulia Orteca ◽  
Federica Pisaneschi ◽  
Sara Rubagotti ◽  
Tracy Liu ◽  
Giacomo Biagiotti ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Human Lymphocytes ◽  
Cancer Cell Line ◽  
Cell Uptake ◽  
In Vivo Studies ◽  
Colorectal Cancer Cell Line ◽  
Preferential Uptake ◽  
Gallium 68

Colorectal cancer is the third most commonly occurring cancer in men and the second most commonly occurring cancer in women worldwide. We have recently reported that curcuminoid complexes labelled with gallium-68 have demonstrated preferential uptake in HT29 colorectal cancer and K562 lymphoma cell lines compared to normal human lymphocytes. In the present study, we report a new gallium-68-labelled curcumin derivative (68Ga-DOTA-C21) and its initial validation as marker for early detection of colorectal cancer. The precursor and non-radioactive complexes were synthesized and deeply characterized by analytical methods then the curcuminoid was radiolabelled with gallium-68. The in vitro stability, cell uptake, internalization and efflux properties of the probe were studied in HT29 cells, and the in vivo targeting ability and biodistribution were investigated in mice bearing HT29 subcutaneous tumour model. 68Ga-DOTA-C21 exhibits decent stability (57 ± 3% after 120 min of incubation) in physiological media and a curcumin-mediated cellular accumulation in colorectal cancer cell line (121 ± 4 KBq of radiotracer per mg of protein within 60 min of incubation). In HT29 tumour-bearing mice, the tumour uptake of 68Ga-DOTA-C21 is 3.57 ± 0.3% of the injected dose per gram of tissue after 90 min post injection with a tumour to muscle ratio of 2.2 ± 0.2. High amount of activity (12.73 ± 1.9% ID/g) is recorded in blood and significant uptake of the radiotracer occurs in the intestine (13.56 ± 3.3% ID/g), lungs (8.42 ± 0.8% ID/g), liver (5.81 ± 0.5% ID/g) and heart (4.70 ± 0.4% ID/g). Further studies are needed to understand the mechanism of accumulation and clearance; however, 68Ga-DOTA-C21 provides a productive base-structure to develop further radiotracers for imaging of colorectal cancer.

scholarly journals The POLD1R689W variant increases the sensitivity of colorectal cancer cells to ATR and CHK1 inhibitors

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Albert Job ◽  
Marina Tatura ◽  
Cora Schäfer ◽  
Veronika Lutz ◽  
Hanna Schneider ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Replication ◽  
Cancer Cells ◽  
Cancer Cell Line ◽  
Colorectal Cancer Cell Line ◽  
Variants Of Unknown Significance ◽  
Pathway Activation ◽  
Synthetic Lethal Interactions

Abstract Inhibition of the kinase ATR, a central regulator of the DNA damage response, eliminates subsets of cancer cells in certain tumors. As previously shown, this is at least partly attributable to synthetic lethal interactions between ATR and POLD1, the catalytic subunit of the polymerase δ. Various POLD1 variants have been found in colorectal cancer, but their significance as therapeutic targets for ATR pathway inhibition remains unknown. Using CRISPR/Cas9 in the colorectal cancer cell line DLD-1, which harbors four POLD1 variants, we established heterozygous POLD1-knockout clones with exclusive expression of distinct variants to determine the functional relevance of these variants individually by assessing their impact on ATR pathway activation, DNA replication, and cellular sensitivity to inhibition of ATR or its effector kinase CHK1. Of the four variants analyzed, only POLD1R689W affected POLD1 function, as demonstrated by compensatory ATR pathway activation and impaired DNA replication. Upon treatment with ATR or CHK1 inhibitors, POLD1R689W strongly decreased cell survival in vitro, which was attributable at least partly to S phase impairment and apoptosis. Similarly, treatment with the ATR inhibitor AZD6738 inhibited growth of murine xenograft tumors, harboring the POLD1R689W variant, in vivo. Our POLD1-knockout model thus complements algorithm-based models to predict the pathogenicity of tumor-specific variants of unknown significance and illustrates a novel and potentially clinically relevant therapeutic approach using ATR/CHK1 inhibitors in POLD1-deficient tumors.

scholarly journals Selection of a Malignant Subpopulation from a Colorectal Cancer Cell Line

2019 ◽  
Author(s):  
Pei-Lun Lai ◽  
Ting-Chun Chen ◽  
Chun-Yen Feng ◽  
Hsuan Lin ◽  
Ng Wu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Line ◽  
Prognostic Biomarker ◽  
Differentially Expressed Gene ◽  
Cancer Cell Line ◽  
Experimental Models ◽  
Colorectal Cancer Cell Line ◽  
Selection Of

AbstractColorectal cancer (CRC) is a leading cause of death from cancer worldwide. Thus, there is an emerging need for new experimental models that allow identification and validation of biomarkers for CRC-specific progression. In this study, we propose a repeated sphere-forming assay as a strategy to select a malignant subpopulation from a CRC line, HCT116. We validated our assay by confirming that three canonical stemness markers, Nanog, Oct4, and Lgr5, were up-regulated in the sphere state at every generation of the selection assay. The resulting line, after eight rounds of selection, exhibited an increased sphere-forming capacityin vitroand tumorgenicityin vivo. Furthermore, dipeptidase 1 (DPEP1) was identified as the major differentially expressed gene in the selected clone, and depletion of DPEP1 suppressed the elevated sphere-forming capacityin vitroand tumorgenicityin vivo. Overall, we have established an experimental strategy for the isolation of a malignant subpopulation from a CRC cell line. Results from our model also suggested that DPEP1 can serve as a promising prognostic biomarker for CRC.

scholarly journals Antiproliferative Effect of Aspirin on Colorectal Cancer Cell Line

2018 ◽  
Vol 12 (5) ◽  
pp. 1-4
Author(s):  
Malihe Bagheri ◽  
◽  
Amir Reza Hesari ◽  
Parisa Zia Sarabi ◽  
Hamid Reza Rahimi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell Line ◽  
Sw480 Cell ◽  
Colorectal Cancer Cell Line ◽  
Range Analysis ◽  
Cytotoxic Effects

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) such as Aspirin may have anticancer properties, and can be effective as a novel strategy for the treatment of colorectal cancer (CRC). The aim of this study was to assess the cytotoxic effects of Aspirin drug in CRC cell lines compared with Oxaliplatin drug in vitro. Methods: Cell viability was assessed after treatment of SW742 and SW480 cells with Aspirin and Oxaliplatin by MTT assay, and the amount of IC50 was determined. Statistical analysis was performed through one-way ANOVA and Tukey multiple range analysis (SPSS 19.0 software (P <0.05). Results: Aspirin and Oxaliplatin considerably inhibited the growth of SW742 and SW480 cell lines. SW742 cell line was more sensitive to Aspirin than SW480 cell line. The cytotoxic effect of Oxaliplatin was higher than Aspirin in both cell lines. Conclusions: This study demonstrated that both Aspirin and Oxaliplatin have cytotoxic effects on SW742 and SW480 cell lines in vitro. Thus, Aspirin may be considered as a therapeutic agent in CRC, however, further in vivo investigations are required to fully establish this effect.

scholarly journals Simulating the human tumor microenvironment in colorectal cancer organoids in vitro and in vivo

2019 ◽  
Author(s):  
Mahesh Devarasetty ◽  
Anthony Dominijanni ◽  
Samuel Herberg ◽  
Ethan Shelkey ◽  
Aleksander Skardal ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Ex Vivo ◽  
Human Tumor ◽  
Cancer Therapeutics ◽  
Low Grade ◽  
Ecm Architecture

AbstractThe tumor microenvironment (TME) plays a significant role in cancer growth and metastasis. Bioengineered models of the TME will advance our understanding of cancer progression and facilitate identification of novel anti-cancer therapeutics that target TME components such as extracellular matrix (ECM) and stromal cells. However, most current in vitro models fail to recapitulate the extensive features of the human tumor stroma, especially ECM architecture, and are not exposed to intact body physiology. On the other hand, in vivo animal models do not accurately capture human tumor architecture. Using the features of biopsied colorectal cancer (CRC) tissue as a guide, we address these deficiencies by creating human organoids containing a colonic stromal ECM layer and CRC spheroids. Organoids were studied in vitro and upon implantation in mice for 28 days. We show that the stromal ECM micro-architecture, generated in vitro, was maintained in vivo for at least 28 days. Furthermore, comparisons with biopsied CRC tumors revealed that organoids with orderly structured TMEs induce an epithelial phenotype in CRC cells, similar to low-grade tumors, compared to a mesenchymal phenotype observed in disordered TMEs, similar to high-grade tumors. Altogether, these results are the first demonstration of replicating the human tumor ECM architecture in biofabricated tumor organoids under ex vivo and in vivo conditions.

scholarly journals RNF141 interacts with KRAS to promote colorectal cancer progression

Oncogene ◽  
2021 ◽  
Author(s):  
Jiuna Zhang ◽  
Xiaoyu Jiang ◽  
Jie Yin ◽  
Shiying Dou ◽  
Xiaoli Xie ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Plasma Membrane ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Critical Role ◽  
Ring Finger ◽  
Immunohistochemical Analysis ◽  
Bimolecular Fluorescence Complementation

AbstractRING finger proteins (RNFs) play a critical role in cancer initiation and progression. RNF141 is a member of RNFs family; however, its clinical significance, roles, and mechanism in colorectal cancer (CRC) remain poorly understood. Here, we examined the expression of RNF141 in 64 pairs of CRC and adjacent normal tissues by real-time PCR, Western blot, and immunohistochemical analysis. We found that there was more expression of RNF141 in CRC tissue compared with its adjacent normal tissue and high RNF141 expression associated with T stage. In vivo and in vitro functional experiments were conducted and revealed the oncogenic role of RNF141 in CRC. RNF141 knockdown suppressed proliferation, arrested the cell cycle in the G1 phase, inhibited migration, invasion and HUVEC tube formation but promoted apoptosis, whereas RNF141 overexpression exerted the opposite effects in CRC cells. The subcutaneous xenograft models showed that RNF141 knockdown reduced tumor growth, but its overexpression promoted tumor growth. Mechanistically, liquid chromatography-tandem mass spectrometry indicated RNF141 interacted with KRAS, which was confirmed by Co-immunoprecipitation, Immunofluorescence assay. Further analysis with bimolecular fluorescence complementation (BiFC) and Glutathione-S-transferase (GST) pull-down assays showed that RNF141 could directly bind to KRAS. Importantly, the upregulation of RNF141 increased GTP-bound KRAS, but its knockdown resulted in a reduction accordingly. Next, we demonstrated that RNF141 induced KRAS activation via increasing its enrichment on the plasma membrane not altering total KRAS expression, which was facilitated by the interaction with LYPLA1. Moreover, KRAS silencing partially abolished the effect of RNF141 on cell proliferation and apoptosis. In addition, our findings presented that RNF141 functioned as an oncogene by upregulating KRAS activity in a manner of promoting KRAS enrichment on the plasma membrane in CRC.

scholarly journals Diethyldithiocarbamate-copper complex (CuET) inhibits colorectal cancer progression via miR-16-5p and 15b-5p/ALDH1A3/PKM2 axis-mediated aerobic glycolysis pathway

Oncogenesis ◽  
2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Xin Huang ◽  
Yichao Hou ◽  
Xiaoling Weng ◽  
Wenjing Pang ◽  
Lidan Hou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Copper Complex ◽  
Aerobic Glycolysis ◽  
Active Role ◽  
Downstream Effector ◽  
Glycolysis Pathway ◽  
Colorectal Cancer Progression

AbstractExploring novel anticancer drugs to optimize the efficacy may provide a benefit for the treatment of colorectal cancer (CRC). Disulfiram (DSF), as an antialcoholism drug, is metabolized into diethyldithiocarbamate-copper complex (CuET) in vivo, which has been reported to exert the anticancer effects on various tumors in preclinical studies. However, little is known about whether CuET plays an anti-cancer role in CRC. In this study, we found that CuET had a marked effect on suppressing CRC progression both in vitro and in vivo by reducing glucose metabolism. Mechanistically, using RNA-seq analysis, we identified ALDH1A3 as a target gene of CuET, which promoted cell viability and the capacity of clonal formation and inhibited apoptosis in CRC cells. MicroRNA (miR)-16-5p and 15b-5p were shown to synergistically regulate ALDH1A3, which was negatively correlated with both of them and inversely correlated with the survival of CRC patients. Notably, using co-immunoprecipitation followed with mass spectrometry assays, we identified PKM2 as a direct downstream effector of ALDH1A3 that stabilized PKM2 by reducing ubiquitination. Taken together, we disclose that CuET treatment plays an active role in inhibiting CRC progression via miR-16-5p and 15b-5p/ALDH1A3/PKM2 axis–mediated aerobic glycolysis pathway.

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