Expression data from tumor samples treated with a tankyrase inhibitor in a mouse xenograft model
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE113965 | GEO | 2018/12/26
REPOSITORIES: GEO
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Project description:Wnt/β-catenin signaling is activated in colorectal cancer (CRC) and is involved in CRC growth. Tankyrase, a poly(ADP-ribose) polymerase family member, destabilizes Axin and positively regulates the Wnt/β-catenin signaling. Tankyrase inhibitors efficiently suppress CRC cell proliferation. We established 320-IWR cells, which showed resistance to tankyrase inhibitor IWR-1, from human CRC COLO-320DM cells. We analyzed gene expression profile of 320-IWR cells (320IWR_1,_2) and parental COLO-320DM cells (COLO320_1,_2).
2016-11-01 | GSE86061 | GEO
Project description:Tankyrase, a poly(ADP-ribose) polymerase family member, destabilizes Axin and positively regulates the Wnt/β-catenin signaling. We demonstrated that tankyrase inhibitors can target the colorectal cancer stem-like cells. Tankyrase inhibitors efficiently suppress colorectal cancer stem-like cell proliferation via AXIN-dependent manner. We sorted CD44-positive COLO-320DM cells, which showed a characteristic of CSCs and were targeted by tankyrase inhibitors. We analyzed gene expression profile of CD44-positive cells (CD44-positive 01, 02, 03) and CD44-negative cells (CD44-negative 01, 02, 03).
2020-05-05 | GSE130750 | GEO
Project description:Embryonic genome activation (EGA) is orchestrated by an intrinsic developmental program initiated during oocyte maturation with translation of stored maternal mRNAs. Here we show that tankyrase, a poly(ADP-ribosyl) polymerase that regulates β-catenin levels, undergoes programmed translation during oocyte maturation and serves an essential role in mouse EGA. Newly translated TNKS triggers proteasomal degradation of axin, reducing targeted destruction of β-catenin and promoting β-catenin-mediated transcription of target genes, including Myc. MYC mediates ribosomal RNA transcription in 2-cell embryos, supporting global protein synthesis. Suppression of tankyrase activity using knockdown or chemical inhibition causes loss of nuclear β-catenin and global reductions in transcription and histone H3 acetylation. Chromatin and transcriptional profiling indicate that development arrests prior to the mid-2-cell stage, mediated in part by reductions in β-catenin and MYC. These findings indicate that post-transcriptional regulation of tankyrase serves as a ligand-independent developmental mechanism for post-translational β-catenin activation and is required to complete EGA.
2020-05-21 | GSE123815 | GEO
Project description:Small-molecule tankyrase 1 and tankyrase 2 (TNKS1/2) inhibitors are effective anti-tumor agents in selected tumor cell lines and mouse models. Here, we characterized the response signatures and the in-depth mechanisms for the anti-proliferative effect of tankyrase inhibition (TNKSi). The TNKS1/2-specific inhibitor G007-LK was used to screen 537 human tumor cell lines and a panel of in particular TNKSi-sensitive tumor cell lines was identified. Transcriptome, proteome and bioinformatic analyses revealed the overall TNKSi-induced response signatures in the selected panel. TNKSi-mediated inhibition of WNT/β-catenin, YAP and PI3K/AKT signaling was validated and correlated with lost expression of the key oncogene MYC and impaired cell growth. Moreover, we show that TNKSi induces accumulation of TNKS1/2-containing β-catenin degradasomes functioning as central complexes interacting with YAP and AMOT proteins during attenuation of YAP signaling. These findings provide a contextual and mechanistic framework for using TNKSi in anti-cancer treatment that warrants further comprehensive preclinical and clinical evaluations.
2021-09-09 | PXD022908 | Pride
Project description:Anti-cancer treatment, using small-molecule tankyrase 1 and tankyrase 2 (TNKS1/2) inhibition (TNKSi) shows effect against selected tumor cell lines and in mouse models. Here, we characterize the responsiveness signatures and in depth mechanisms for the anti-proliferative effect of TNKSi. The TNKS1/2-specific inhibitor G007-LK was screened against 537 human tumor cell lines, and a panel of in particular TNKSi-sensitive tumor cell lines was identified. Transcriptome, proteome and bioinformatic analyses classified the overall TNKSi-induced response signatures in the selected panel. Prediction of TNKSi-mediated inhibition of WNT/β-catenin, YAP and PI3K/AKT signaling was validated and correlated with lost expression of the key oncogene MYC and impaired cell growth. Moreover, we show that TNKSi, when attenuating YAP signaling, induces accumulation of TNKS1/2-containing β-catenin degradosomes functioning as central complexes interacting with YAP and AMOT proteins. The findings provide a contextual and mechanistic framework for TNKSi in cancer cell lines rationalizing further comprehensive preclinical and clinical evaluations.
2021-06-18 | GSE162648 | GEO
Project description:Tankyrase, a poly(ADP-ribose) polymerase family member, regulates multiple cellular processes. Tankyrase inhibitors efficiently suppress colorectal cancer (CRC) cell proliferation. To examine the mechanism of anti-proliferative effect of tankyrase inhibitors (G007LK and RK582), we analyzed gene expression profiles of patient-derived CRC cells (JC11 and JC494) left untreated or treated with 0.3 µM G007LK or RK582 for 24 h by cDNA microarray analysis.
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Project description:Tankyrase, a poly(ADP-ribose) polymerase family member, regulates multiple cellular processes. Tankyrase inhibitors efficiently suppress APC-mutated colorectal cancer (CRC) cell proliferation. To examine the mechanism of anti-proliferative effect of tankyrase inhibitors (G007LK and RK582), we analyzed gene expression profiles of patient-derived APC-mutated CRC cells (JC21 and JC475) left untreated or treated with 0.3 µM G007LK or RK582 for 24 h by cDNA microarray analysis.
2024-01-17 | GSE232209 | GEO
Project description:Strong activation of the oncogenic Wnt/beta-catenin pathway is a main mechanism of resistance to FOXO3a-induced apoptosis promoted by PI3K and AKT inhibitors in colorectal cancer (CRC). Reducing Wnt/beta-catenin activity would sensitize colorectal tumors to these inhibitors. However, no Wnt/beta-catenin signaling inhibitor has proven clinical potential yet. Recently, inhibitors that block tankyrases were shown to reduce colon cancer cell proliferation by decreasing nuclear beta-catenin. We aim to identify determinants of response to these novel Wnt-inhibitors. Therefore, we treated in vivo three different patient-derived xenograft models (PDX; P2, P5 and P30) growing subcutaneously in NOD SCID mice with the novel tankyrase inhibitor NVP-TNKS656.
2015-08-10 | E-MTAB-2446 | biostudies-arrayexpress
Project description:Lee2003 - Roles of APC and Axin in Wnt
Pathway (without regulatory loop)
This model is described in the article:
The roles of APC and Axin
derived from experimental and theoretical analysis of the Wnt
pathway.
Lee E, Salic A, Krüger R,
Heinrich R, Kirschner MW.
PLoS Biol. 2003 Oct; 1(1): E10
Abstract:
Wnt signaling plays an important role in both oncogenesis
and development. Activation of the Wnt pathway results in
stabilization of the transcriptional coactivator beta-catenin.
Recent studies have demonstrated that axin, which coordinates
beta-catenin degradation, is itself degraded. Although the key
molecules required for transducing a Wnt signal have been
identified, a quantitative understanding of this pathway has
been lacking. We have developed a mathematical model for the
canonical Wnt pathway that describes the interactions among the
core components: Wnt, Frizzled, Dishevelled, GSK3beta, APC,
axin, beta-catenin, and TCF. Using a system of differential
equations, the model incorporates the kinetics of
protein-protein interactions, protein synthesis/degradation,
and phosphorylation/dephosphorylation. We initially defined a
reference state of kinetic, thermodynamic, and flux data from
experiments using Xenopus extracts. Predictions based on the
analysis of the reference state were used iteratively to
develop a more refined model from which we analyzed the effects
of prolonged and transient Wnt stimulation on beta-catenin and
axin turnover. We predict several unusual features of the Wnt
pathway, some of which we tested experimentally. An insight
from our model, which we confirmed experimentally, is that the
two scaffold proteins axin and APC promote the formation of
degradation complexes in very different ways. We can also
explain the importance of axin degradation in amplifying and
sharpening the Wnt signal, and we show that the dependence of
axin degradation on APC is an essential part of an
unappreciated regulatory loop that prevents the accumulation of
beta-catenin at decreased APC concentrations. By applying
control analysis to our mathematical model, we demonstrate the
modular design, sensitivity, and robustness of the Wnt pathway
and derive an explicit expression for tumor suppression and
oncogenicity.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000658.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2018-03-20 | BIOMD0000000658 | BioModels
Project description:Tankyrase 1 (TNKS1) and tankyrase 2 (TNKS2) belong to the poly(ADP-ribose) polymerase (PARP) family of proteins, which use NAD+ to modify substrate proteins with ADP-ribose modifications. Tankyrases are implicated involving in multiple cellular functions, including the telomere length control, Wnt/b-catenin pathway regulation, glucose uptake and cell cycle regulation. Emerging evidences reveal the pathological relevance of tankyrase in diseases and propose these two key enzymes as potential drug targets. However, the cellular functions and regulatory machineries of tankyrases are still largely unknown. Through this proteomic analysis, we not only defined the protein-protein interaction map for the tankyrases which revealed 100~150 high confident interacting proteins for tankyrases in various cellular functions, but also uncovered the novel regulating function of tankyrase in peroxisome homeostasis.
2017-07-24 | PXD004647 | Pride