scholarly journals Molecular mechanism and potential target indication of TAK-931, a novel CDC7-selective inhibitor

2019 ◽  
Vol 5 (5) ◽  
pp. eaav3660 ◽  
Author(s):  
Kenichi Iwai ◽  
Tadahiro Nambu ◽  
Ryo Dairiki ◽  
Momoko Ohori ◽  
Jie Yu ◽  
...  
Keyword(s):  
Panel Data ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Selective Inhibitor ◽  
Chemotherapeutic Drugs ◽  
Comparison Analysis ◽  
Antiproliferative Effects ◽  
Potential Target ◽  
Preclinical Animal Models ◽  
Cell Division Cycle 7

Replication stress (RS) is a cancer hallmark; chemotherapeutic drugs targeting RS are widely used as treatments for various cancers. To develop next-generation RS-inducing anticancer drugs, cell division cycle 7 (CDC7) has recently attracted attention as a target. We have developed an oral CDC7-selective inhibitor, TAK-931, as a candidate clinical anticancer drug. TAK-931 induced S phase delay and RS. TAK-931–induced RS caused mitotic aberrations through centrosome dysregulation and chromosome missegregation, resulting in irreversible antiproliferative effects in cancer cells. TAK-931 exhibited significant antiproliferative activity in preclinical animal models. Furthermore, in indication-seeking studies using large-scale cell panel data, TAK-931 exhibited higher antiproliferative activities in RAS-mutant versus RAS–wild-type cells; this finding was confirmed in pancreatic patient-derived xenografts. Comparison analysis of cell panel data also demonstrated a unique efficacy spectrum for TAK-931 compared with currently used chemotherapeutic drugs. Our findings help to elucidate the molecular mechanisms for TAK-931 and identify potential target indications.

scholarly journals EGCG binds intrinsically disordered N-terminal domain of p53 and disrupts p53-MDM2 interaction

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jing Zhao ◽  
Alan Blayney ◽  
Xiaorong Liu ◽  
Lauren Gandy ◽  
Weihua Jin ◽  
...  
Keyword(s):  
Large Scale ◽  
Molecular Mechanisms ◽  
Epigallocatechin Gallate ◽  
Cancer Drug ◽  
Dynamic Interactions ◽  
Cancer Drug Discovery ◽  
Intrinsically Disordered ◽  
Terminal Domain ◽  
Cancerous Cells

AbstractEpigallocatechin gallate (EGCG) from green tea can induce apoptosis in cancerous cells, but the underlying molecular mechanisms remain poorly understood. Using SPR and NMR, here we report a direct, μM interaction between EGCG and the tumor suppressor p53 (KD = 1.6 ± 1.4 μM), with the disordered N-terminal domain (NTD) identified as the major binding site (KD = 4 ± 2 μM). Large scale atomistic simulations (>100 μs), SAXS and AUC demonstrate that EGCG-NTD interaction is dynamic and EGCG causes the emergence of a subpopulation of compact bound conformations. The EGCG-p53 interaction disrupts p53 interaction with its regulatory E3 ligase MDM2 and inhibits ubiquitination of p53 by MDM2 in an in vitro ubiquitination assay, likely stabilizing p53 for anti-tumor activity. Our work provides insights into the mechanisms for EGCG’s anticancer activity and identifies p53 NTD as a target for cancer drug discovery through dynamic interactions with small molecules.

scholarly journals Integrative cBioPortal Analysis Revealed Molecular Mechanisms That Regulate EGFR-PI3K-AKT-mTOR Pathway in Diffuse Gliomas of the Brain

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3247
Author(s):  
Petar Brlek ◽  
Anja Kafka ◽  
Anja Bukovac ◽  
Nives Pećina-Šlaus
Keyword(s):  
Large Scale ◽  
Molecular Mechanisms ◽  
In Silico Analysis ◽  
Total Sample ◽  
Mtor Signaling ◽  
Biological Behavior ◽  
Mrna Transcription ◽  
Diffuse Gliomas ◽  
New Treatment ◽  
Using Data

Diffuse gliomas are a heterogeneous group of tumors with aggressive biological behavior and a lack of effective treatment methods. Despite new molecular findings, the differences between pathohistological types still require better understanding. In this in silico analysis, we investigated AKT1, AKT2, AKT3, CHUK, GSK3β, EGFR, PTEN, and PIK3AP1 as participants of EGFR-PI3K-AKT-mTOR signaling using data from the publicly available cBioPortal platform. Integrative large-scale analyses investigated changes in copy number aberrations (CNA), methylation, mRNA transcription and protein expression within 751 samples of diffuse astrocytomas, anaplastic astrocytomas and glioblastomas. The study showed a significant percentage of CNA in PTEN (76%), PIK3AP1 and CHUK (75% each), EGFR (74%), AKT2 (39%), AKT1 (32%), AKT3 (19%) and GSK3β (18%) in the total sample. Comprehensive statistical analyses show how genomics and epigenomics affect the expression of examined genes differently across various pathohistological types and grades, suggesting that genes AKT3, CHUK and PTEN behave like tumor suppressors, while AKT1, AKT2, EGFR, and PIK3AP1 show oncogenic behavior and are involved in enhanced activity of the EGFR-PI3K-AKT-mTOR signaling pathway. Our findings contribute to the knowledge of the molecular differences between pathohistological types and ultimately offer the possibility of new treatment targets and personalized therapies in patients with diffuse gliomas.

scholarly journals Antihyperglycaemic therapies and cancer risk

2014 ◽  
Vol 11 (6) ◽  
pp. 371-389 ◽  
Author(s):  
Stefan Z Lutz ◽  
Harald Staiger ◽  
Andreas Fritsche ◽  
Hans-Ulrich Häring
Keyword(s):  
Cancer Risk ◽  
Large Scale ◽  
Tumour Growth ◽  
Molecular Mechanisms ◽  
Growth Promotion ◽  
Protective Effects ◽  
Antidiabetic Drug ◽  
Safety Issues ◽  
Drug Classes ◽  
Few Data

Aims: This review is aimed at highlighting the potential mitogenic/tumour growth–promoting or antimitogenic/tumour growth–inhibiting effects of the main antihyperglycaemic drug classes. Methods: We review and discuss the most current studies evaluating the association between antidiabetic medications used in clinical practice and malignancies as described so far. Results: Metformin seems to be the only antidiabetic drug to exert protective effects both on monotherapy and also when combined with other oral antidiabetic drugs or insulins in several site-specific cancers. In contrast, several other drug classes may increase cancer risk. Some reason for concern remains regarding sulphonylureas and also the incretin-based therapies regarding pancreas and thyroid cancers and the sodium glucose cotransporter-2 inhibitors as well as pioglitazone regarding bladder cancer. The majority of meta-analyses suggest that there is no evidence for a causal relationship between insulin glargine and elevated cancer risk, although the studies have been controversially discussed. For α-glucosidase inhibitors and glinides, neutral or only few data upon cancer risk exist. Conclusion: Although the molecular mechanisms are not fully understood, a potential risk of mitogenicity and tumour growth promotion cannot be excluded in case of several antidiabetic drug classes. However, more large-scale, randomized, well-designed clinical studies with especially long follow-up time periods are needed to get reliable answers to these safety issues.

Sex differences in white adipose tissue expansion: emerging molecular mechanisms

2021 ◽  
Vol 135 (24) ◽  
pp. 2691-2708
Author(s):  
Simon T. Bond ◽  
Anna C. Calkin ◽  
Brian G. Drew
Keyword(s):  
Sex Differences ◽  
Sexual Dimorphism ◽  
Gene Networks ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Tissue Expansion ◽  
Economic Systems ◽  
Genomic Association ◽  
Males And Females

Abstract The escalating prevalence of individuals becoming overweight and obese is a rapidly rising global health problem, placing an enormous burden on health and economic systems worldwide. Whilst obesity has well described lifestyle drivers, there is also a significant and poorly understood component that is regulated by genetics. Furthermore, there is clear evidence for sexual dimorphism in obesity, where overall risk, degree, subtype and potential complications arising from obesity all differ between males and females. The molecular mechanisms that dictate these sex differences remain mostly uncharacterised. Many studies have demonstrated that this dimorphism is unable to be solely explained by changes in hormones and their nuclear receptors alone, and instead manifests from coordinated and highly regulated gene networks, both during development and throughout life. As we acquire more knowledge in this area from approaches such as large-scale genomic association studies, the more we appreciate the true complexity and heterogeneity of obesity. Nevertheless, over the past two decades, researchers have made enormous progress in this field, and some consistent and robust mechanisms continue to be established. In this review, we will discuss some of the proposed mechanisms underlying sexual dimorphism in obesity, and discuss some of the key regulators that influence this phenomenon.

scholarly journals Current Strategies for Identification of Glioma Stem Cells: Adequate or Unsatisfactory?

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Paola Brescia ◽  
Cristina Richichi ◽  
Giuliana Pelicci
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Cell Phenotype ◽  
Multiple Tumor ◽  
Early Results ◽  
Tumorigenic Potential ◽  
Tumor Types

Cancer stem cells (CSCs) were isolated in multiple tumor types, including human glioblastomas, and although the presence of surface markers selectively expressed on CSCs can be used to isolate them, no marker/pattern of markers are sufficiently robust to definitively identify stem cells in tumors. Several markers were evaluated for their prognostic value with promising early results, however none of them was proven to be clinically useful in large-scale studies, leading to outstanding efforts to identify new markers. Given the heterogeneity of human glioblastomas further investigations are necessary to identify both cancer stem cell-specific markers and the molecular mechanisms sustaining the tumorigenic potential of these cells to develop tailored treatments. Markers for glioblastoma stem cells such as CD133, CD15, integrin-α6, L1CAM might be informative to identify these cells but cannot be conclusively linked to a stem cell phenotype. Overlap of expression, functional state and morphology of different subpopulations lead to carefully consider the techniques employed so far to isolate these cells. Due to a dearth of methods and markers reliably identifying the candidate cancer stem cells, the isolation/enrichment of cancer stem cells to be therapeutically targeted remains a major challenge.

scholarly journals Inhibition of iNOS protects against the deleterious effects of sub-lethal sepsis and ethanol in the cardiorenal system

2021 ◽  
Author(s):  
Arthur H. Sousa ◽  
Gabriel T. Do Vale ◽  
Jose A Nascimento ◽  
Wanessa Mayumi Carvalho Awata ◽  
Carla Brigagão Pacheco da Silva ◽  
...  
Keyword(s):  
Biochemical Analysis ◽  
Molecular Mechanisms ◽  
Renal Cortex ◽  
Cecal Ligation ◽  
Selective Inhibitor ◽  
Oxygen Species ◽  
Cecal Ligation And Puncture ◽  
Post Surgery ◽  
Lethal Sepsis ◽  
Pro Inflammatory Cytokines

We tested the hypothesis that ethanol would aggravate the deleterious effects of sub-lethal cecal ligation and puncture (SL-CLP) sepsis in the cardiorenal system and that inhibition of iNOS would prevent such response. Male C57BL/6 mice were treated with ethanol for 12 weeks. One hour before SL-CLP surgery, mice were treated with N6-(1-Iminoethyl)-lysine (L-NIL, 5 mg/kg, i.p), a selective inhibitor of iNOS. A second dose of L-NIL was administered 24 h after SL-CLP surgery. Mice were killed 48 h post-surgery and blood, the renal cortex and left ventricle (LV) were collected for biochemical analysis. L-NIL attenuated the increase in serum creatinine levels induced by ethanol, but not by SL-CLP. Ethanol, but not SL-CLP increased creatine kinase (CK)-MB activity and L-NIL did not prevent this response. In the renal cortex, L-NIL prevented the redox imbalance induced by ethanol and SL-CLP. Inhibition of iNOS also decreased lipoperoxidation induced by ethanol and SL-CLP in the LV. L-NIL prevented the increase of pro-inflammatory cytokines and reactive oxygen species (ROS) induced by ethanol and/or SL-CLP in the cardiorenal system, suggesting that iNOS modulated some of the molecular mechanisms that underlie the deleterious effects of both conditions in the cardiorenal system.

scholarly journals Synaptonemal Complex dimerization regulates chromosome alignment and crossover patterning in meiosis

2020 ◽  
Author(s):  
Spencer G. Gordon ◽  
Lisa E. Kursel ◽  
Kewei Xu ◽  
Ofer Rog
Keyword(s):  
Synaptonemal Complex ◽  
Sequence Homology ◽  
Genetic Information ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Homologous Chromosomes ◽  
C Elegans ◽  
Local Sequence ◽  
Chromosome Alignment ◽  
Dimerization Interface

AbstractDuring sexual reproduction the parental homologous chromosomes find each other (pair) and align along their lengths by integrating local sequence homology with large-scale contiguity, thereby allowing for precise exchange of genetic information. The Synaptonemal Complex (SC) is a conserved zipper-like structure that assembles between the homologous chromosomes. This phase-separated interface brings chromosomes together and regulates exchanges between them. However, the molecular mechanisms by which the SC carries out these functions remain poorly understood. Here we isolated and characterized two mutations in the dimerization interface in the middle of the SC zipper in C. elegans. The mutations perturb both chromosome alignment and the regulation of genetic exchanges. Underlying the chromosome-scale phenotypes are distinct alterations to the way SC subunits interact with one another. We propose that the SC brings homologous chromosomes together through two biophysical activities: obligate dimerization that prevents assembly on unpaired chromosomes; and a tendency to phase-separate that extends pairing interactions along the entire length of the chromosomes.

scholarly journals Molecular Inverse Comorbidity between Alzheimer’s disease and Lung Cancer: new insights from Matrix Factorization

2019 ◽  
Author(s):  
Alessandro Greco ◽  
Jon Sanchez Valle ◽  
Vera Pancaldi ◽  
Anaïs Baudot ◽  
Emmanuel Barillot ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Matrix Factorization ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Biological Data ◽  
Biological Data Analysis ◽  
Specific Factors ◽  
Molecular Bases

AbstractMatrix Factorization (MF) is an established paradigm for large-scale biological data analysis with tremendous potential in computational biology.We here challenge MF in depicting the molecular bases of epidemiologically described Disease-Disease (DD) relationships. As use case, we focus on the inverse comorbidity association between Alzheimer’s disease (AD) and lung cancer (LC), described as a lower than expected probability of developing LC in AD patients. To the day, the molecular mechanisms underlying DD relationships remain poorly explained and their better characterization might offer unprecedented clinical opportunities.To this goal, we extend our previously designed MF-based framework for the molecular characterization of DD relationships. Considering AD-LC inverse comorbidity as a case study, we highlight multiple molecular mechanisms, among which the previously identified immune system and mitochondrial metabolism. We then discriminate mechanisms specific to LC from those shared with other cancers through a pancancer analysis. Additionally, new candidate molecular players, such as Estrogen Receptor (ER), CDH1 and HDAC, are pinpointed as factors that might underlie the inverse relationship, opening the way to new investigations. Finally, some lung cancer subtype-specific factors are also detected, suggesting the existence of heterogeneity across patients also in the context of inverse comorbidity.

scholarly journals Dual RNA-seq reveals large-scale non-conserved genotype x genotype specific genetic reprograming and molecular crosstalk in the mycorrhizal symbiosis

2018 ◽  
Author(s):  
Ivan D. Mateus ◽  
Frédéric G. Masclaux ◽  
Consolée Aletti ◽  
Edward C. Rojas ◽  
Romain Savary ◽  
...  
Keyword(s):  
Mycorrhizal Fungi ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Arbuscular Mycorrhizal ◽  
Mycorrhizal Symbiosis ◽  
Rna Seq ◽  
Plant Host ◽  
Transcriptional Responses ◽  
Plant Genes ◽  
Fungal Genetic

AbstractArbuscular mycorrhizal fungi (AMF) impact plant growth and are a major driver of plant diversity and productivity. We quantified the contribution of intra-specific genetic variability in cassava (Manihot esculenta) and Rhizophagus irregularis to gene reprogramming in symbioses using dual RNA-sequencing. A large number of cassava genes exhibited altered transcriptional responses to the fungus but transcription of most of these plant genes (72%) responded in a different direction or magnitude depending on the plant genotype. Two AMF isolates displayed large differences in their transcription, but the direction and magnitude of the transcriptional responses for a large number of these genes was also strongly influenced by the genotype of the plant host. This indicates that unlike the highly conserved plant genes necessary for the symbiosis establishment, plant and fungal gene transcriptional responses are not conserved and are greatly influenced by plant and fungal genetic differences, even at the within-species level. The transcriptional variability detected allowed us to identify an extensive gene network showing the interplay in plant-fungal reprogramming in the symbiosis. Key genes illustrated that the two organisms jointly program their cytoskeleton organisation during growth of the fungus inside roots. Our study reveals that plant and fungal genetic variation plays a strong role in shaping the genetic reprograming in response to symbiosis, indicating considerable genotype x genotype interactions in the mycorrhizal symbiosis. Such variation needs to be considered in order to understand the molecular mechanisms between AMF and their plant hosts in natural communities.

scholarly journals Reference genome assemblies reveal the origin and evolution of allohexaploid oat

2021 ◽  
Author(s):  
Yuanying Peng ◽  
Honghai Yan ◽  
Laichun Guo ◽  
Cao Deng ◽  
Lipeng Kang ◽  
...  
Keyword(s):  
Large Scale ◽  
Molecular Mechanisms ◽  
Higher Plants ◽  
Cereal Crops ◽  
Origin And Evolution ◽  
Avena Species ◽  
Oxford Nanopore ◽  
Reference Quality ◽  
Phylogenomic Analyses ◽  
Reference Genomes

Abstract Common oat (Avena sativa) is one of the most important cereal crops serving as a valuable source of forage and human food. While reference genomes of many important crops have been generated, such work in oat has lagged behind, primarily owing to its large, repeat-rich, polyploid genome. By using Oxford Nanopore ultralong sequencing and Hi-C technologies, we have generated the first reference-quality genome assembly of hulless common oat with a contig N50 of 93 Mb. We also assembled the genomes of diploid and tetraploid Avena ancestors, which enabled us to identify oat subgenome, large-scale structural rearrangements, and preferential gene loss in the C subgenome after hexaploidization. Phylogenomic analyses of cereal crops indicated that the oat lineage descended before wheat, offering oat as a unique window into the early evolution of polyploid plants. The origin and evolution of hexaploid oat is deduced from whole-genome sequencing, plastid genome and transcriptomes assemblies of numerous Avena species. The high-quality reference genomes of Avena species with different ploidies and the studies of their polyploidization history will facilitate the full use of crop gene resources and provide a reference for the molecular mechanisms underlying the polyploidization of higher plants, helping us to overcome food security challenges.

Sign in / Sign up

Export Citation Format

Share Document