scholarly journals Tankyrase inhibition sensitizes cells to CDK4 blockade

2019 ◽  
Author(s):  
Miguel Foronda ◽  
Yusuke Tarumoto ◽  
Emma M. Schatoff ◽  
Benjamin I. Leach ◽  
Bianca J Diaz ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Human Cancer ◽  
Human Cancer Cell Lines ◽  
Cycle Arrest ◽  
Crispr Screen ◽  
Positive Regulators ◽  
Cancer Types ◽  
G1 Cell Cycle Arrest ◽  
Canonical Wnt ◽  
Cdk4 Inhibition

AbstractTankyrase (TNKS) 1/2 are positive regulators of WNT signaling by controlling the activity of the β-catenin destruction complex. TNKS inhibitors provide an opportunity to suppress hyperactive WNT signaling in tumors, however, they have shown limited anti-proliferative activity as a monotherapy in human cancer cell lines. Here we perform a kinome-focused CRISPR screen to identify potential effective drug combinations with TNKS inhibition. We show that the loss of CDK4, but not CDK6, synergizes with TNKS1/2 blockade to drive G1 cell cycle arrest and senescence. Through precise modelling of cancer-associated mutations using cytidine base editors, we show that this therapeutic approach is absolutely dependent on suppression of canonical WNT signaling by TNKS inhibitors and is effective in cells from multiple epithelial cancer types. Together, our results suggest that combined WNT and CDK4 inhibition might provide a potential therapeutic strategy for difficult-to-treat epithelial tumors.

scholarly journals Transporter associated with antigen processing 1 (TAP1) expression and prognostic analysis in breast, lung, liver, and ovarian cancer

2021 ◽  
Author(s):  
Anika Tabassum ◽  
Md. Nazmus Samdani ◽  
Tarak Chandra Dhali ◽  
Rahat Alam ◽  
Foysal Ahammad ◽  
...  
Keyword(s):  
Expression Pattern ◽  
Cancer Progression ◽  
Antigen Processing ◽  
Human Cancer ◽  
Analytical Data ◽  
Significant Negative Correlation ◽  
Cancer Tissue ◽  
Human Cancer Cell Lines ◽  
Prognostic Analysis ◽  
Cancer Types

Abstract Transporter associated with antigen processing 1 (TAP1) is a transporter protein that represent tumor antigen in the MHC I or HLA complex. Any defect in the TAP1 gene resulting in inadequate tumor tracking. TAP1 influences multidrug resistance (MDR) in human cancer cell lines and hinders the treatment during chemotherapeutic. The association of TAP1 in cancer progression remains mostly unknown and further study of the gene in relation with cancer need to conduct. Thus, the study has designed to analyze the association between the TAP1 with cancer by computationally. The expression pattern of the gene has determined by using ONCOMINE, GENT2, and GEPIA2 online platforms. The protein level of TAP1 was examined by the help of Human Protein Atlas. Samples with different clinical outcomes were investigated to evaluate the expression and promoter methylation in cancer vs. normal tissues by using UALCAN server. The copy number alteration, mutation frequency, and expression level of the gene in different cancer were analyzed by using cBioPortal server. The PrognoScan and KM plotter platforms were used to perform the survival analysis and represented graphically. Additionally, pathway and gene ontology (GO) features correlated to the TAP1 gene were analyzed and presented by bar charts. After arranging the data in a single panel like correlating expression to prognosis, mutational and alterations characteristic, and pathways analysis, we observed some interesting insights that emphasized the importance of the gene in cancer progression. The study found the relationship between the TAP1 expression pattern and prognosis in different cancer tissues and shows how TAP1 affects the clinical characteristics. The analytical data presented in the study is vital to learn about the effect of TAP1 in tumor tissue, where previously studies showing contradicting expression of TAP1 in cancer tissue. The analyzed data can also be utilized further to evade the threats against chemotherapy. Overall, the study provided a new aspect to consider the role of TAP1 gene in cancer progression and survival status. Key messages • This study demonstrated, for the first time, a correlation between the TAP1 gene and tumor progression. • An upregulation of TAP1 mRNA was demonstrated in various cancer types. • This study reported a significant negative correlation for TAP1 gene expression and the survival rate in different cancer types.

scholarly journals CRISPR enriches for cells with mutations in a p53-related interactome, and this can be inhibited

2021 ◽  
Author(s):  
Long Jiang ◽  
Katrine Ingelshed ◽  
Yunbing Shen ◽  
Sanjaykumar V. Boddul ◽  
Vaishnavi Srinivasan Iyer ◽  
...  
Keyword(s):  
Cellular Response ◽  
Human Cancer ◽  
Genetic Alterations ◽  
Dna Breaks ◽  
Data Set ◽  
Human Cancer Cell Lines ◽  
Cycle Arrest ◽  
Double Stranded Dna ◽  
A Cell

CRISPR/Cas9 can be used to inactivate or modify genes by inducing double-stranded DNA breaks1–3. As a protective cellular response, DNA breaks result in p53-mediated cell cycle arrest and activation of cell death programs4,5. Inactivating p53 mutations are the most commonly found genetic alterations in cancer, highlighting the important role of the gene6–8. Here, we show that cells deficient in p53, as well as in genes of a core CRISPR-p53 tumor suppressor interactome, are enriched in a cell population when CRISPR is applied. Such enrichment could pose a challenge for clinical CRISPR use. Importantly, we identify that transient p53 inhibition suppresses the enrichment of cells with these mutations. Furthermore, in a data set of >800 human cancer cell lines, we identify parameters influencing the enrichment of p53 mutated cells, including strong baseline CDKN1A expression as a predictor for an active CRISPR-p53 axis. Taken together, our data identify strategies enabling safe CRISPR use.

Oleiferasaponin C6 from the seeds of Camellia oleifera Abel.: a novel compound inhibits proliferation through inducing cell-cycle arrest and apoptosis on human cancer cell lines in vitro

RSC Advances ◽  
2016 ◽  
Vol 6 (94) ◽  
pp. 91386-91393 ◽  
Author(s):  
Jianfa Zong ◽  
Dongxu Wang ◽  
Weiting Jiao ◽  
Liang Zhang ◽  
Guanhu Bao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Camellia Oleifera ◽  
Human Cancer Cell Lines ◽  
Cycle Arrest

Oleiferasaponin C6 was isolated from Camellia oleifera Abel. and inhibits proliferation through inducing cell-cycle arrest and apoptosis on cancer cell lines in vitro.

Molecular mechanisms of G0/G1 cell-cycle arrest and apoptosis induced by terfenadine in human cancer cells

2003 ◽  
Vol 37 (1) ◽  
pp. 39-50 ◽  
Author(s):  
Jean-Dean Liu ◽  
Ying-Jan Wang ◽  
Chien-Ho Chen ◽  
Cheng-Fei Yu ◽  
Li-Ching Chen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Human Cancer Cells ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest

scholarly journals Prioritisation of oncology therapeutic targets using CRISPR-Cas9 screening

2018 ◽  
Author(s):  
Fiona M Behan ◽  
Francesco Iorio ◽  
Emanuel Gonçalves ◽  
Gabriele Picco ◽  
Charlotte M Beaver ◽  
...  
Keyword(s):  
Drug Development ◽  
Werner Syndrome ◽  
Human Cancer ◽  
Target Identification ◽  
Recq Helicase ◽  
Human Cancer Cell Lines ◽  
Fitness Effects ◽  
Candidate Target ◽  
Cancer Types ◽  
Genome Scale

SummaryFunctional genomics approaches can overcome current limitations that hamper oncology drug development such as lack of robust target identification and clinical efficacy. Here we performed genome-scale CRISPR-Cas9 screens in 204 human cancer cell lines from 12 cancer-types and developed a data-driven framework to prioritise cancer therapeutic candidates. We integrated gene cell fitness effects with genomic biomarkers and target tractability for drug development to systematically prioritise new oncology targets in defined tissues and genotypes. Furthermore, we took one of our most promising dependencies, Werner syndrome RecQ helicase, and verified it as a candidate target for tumours with microsatellite instability. Our analysis provides a comprehensive resource of cancer dependencies, a framework to prioritise oncology targets, and nominates specific new candidates. The principles described in this study can transform the initial stages of the drug development process contributing to a new, diverse and more effective portfolio of oncology targets.

scholarly journals BRG1 mutations found in human cancer cell lines inactivate Rb-mediated cell-cycle arrest

2011 ◽  
Vol 226 (8) ◽  
pp. 1989-1997 ◽  
Author(s):  
Christopher Bartlett ◽  
Tess J. Orvis ◽  
Gary S. Rosson ◽  
Bernard E. Weissman
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines ◽  
Cycle Arrest
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