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https://www.readbyqxmd.com/read/29048660/canonical-and-non-canonical-wnt-signaling-in-cancer-stem-cells-and-their-niches-cellular-heterogeneity-omics-reprogramming-targeted-therapy-and-tumor-plasticity-review
#1
Masaru Katoh
Cancer stem cells (CSCs), which have the potential for self-renewal, differentiation and de-differentiation, undergo epigenetic, epithelial-mesenchymal, immunological and metabolic reprogramming to adapt to the tumor microenvironment and survive host defense or therapeutic insults. Intra-tumor heterogeneity and cancer-cell plasticity give rise to therapeutic resistance and recurrence through clonal replacement and reactivation of dormant CSCs, respectively. WNT signaling cascades cross-talk with the FGF, Notch, Hedgehog and TGFβ/BMP signaling cascades and regulate expression of functional CSC markers, such as CD44, CD133 (PROM1), EPCAM and LGR5 (GPR49)...
September 19, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/29043869/identifying-the-biomarker-potential-of-telomerase-activity-and-shelterin-complex-molecule-telomeric-repeat-binding-factor-2-terf2-in-multiple-myeloma
#2
Raman Kumar, Rehan Khan, Nidhi Gupta, Tulika Seth, Atul Sharma, Mani Kalaivani, Alpana Sharma
Telomere length (TL) is maintained by telomere capping protein complex called shelterin complex. We studied the possible involvement and biomarker potential of shelterin complex molecules in naive multiple myeloma (MM) patients and controls. TL, relative telomerase activity (RTA), real-time PCR and Western blotting were performed in bonemarrow sample of 70 study subjects (patients = 50; controls = 20). Significantly lowered mean TL, increased RTA and higher mRNA expression of shelterin molecules were observed in patients, while PIN2/TERF1 interacting telomerase inhibitor 1 (PINX1) showed lower mRNA expression...
October 18, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28986473/mouse-red-blood-cell-mediated-rare-xenobiotic-phosphorylation-of-a-drug-molecule-not-intended-to-be-a-kinase-substrate
#3
Chungang Gu, Shenghua Wen, Peter Doig, Eric Gangl, Xiaolan Zheng, Yanjun Wang, Jeffrey W Johannes
Phosphorylation of xenobiotics is rare, probably due to a strong evolutionary pressure against it. This rarity may have attracted more attention recently, owing to intentionally designed kinase-substrate analogs which depend on kinase-catalyzed activation to form phosphorylated active drugs. We report a rare phosphorylated metabolite observed unexpectedly in mouse plasma samples after an oral dose of a Tankyrase inhibitor that was not intended to be a kinase substrate, i.e. (S)-2-(4-(6-(3,4-dimethylpiperazin-1-yl)-4-methylpyridin-3-yl)phenyl)-8-(hydroxymethyl)quinazolin-4(3H)-one (AZ2381)...
October 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28910490/regulation-of-wnt-%C3%AE-catenin-signalling-by-tankyrase-dependent-poly-adp-ribosyl-ation-and-scaffolding
#4
REVIEW
Laura Mariotti, Katie Pollock, Sebastian Guettler
The Wnt/β-catenin signalling pathway is pivotal for stem cell function and the control of cellular differentiation, both during embryonic development and tissue homeostasis in adults. Its activity is carefully controlled through the concerted interactions of concentration-limited pathway components and a wide range of posttranslational modifications, including phosphorylation, ubiquitylation, sumoylation, poly(ADP-ribosyl)ation (PARylation) and acetylation. Regulation of Wnt/β-catenin signalling by PARylation was discovered relatively recently...
September 14, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28900081/-mir-218-promoted-the-apoptosis-of-human-ovarian-carcinoma-cells-via-suppression-of-the-wnt-%C3%AE-catenin-signaling-pathway
#5
Y Huang, S-H Liang, L-B Xiang, X-T Han, W Zhang, J Tang, X-H Wu, M-Q Zhang
MicroRNA-218 (miR-218) is a short, noncoding RNA, with multiple biological functions. In this study, we aimed to investigate the potential effects of miR-218 on the apoptosis of human ovarian carcinoma cells and the underlying mechanisms by which miR-218 exerted its actions. After over-expressing miR-218 in human ovarian carcinoma (OVCAR3) cells, cell viability was determined by MTT method, cell apoptosis was observed by flow cytometry (FCM), mRNA expression of miR-218, Bcl2, Bax was measured by RT-PCR and protein expression levels of Wnt, tankyrase and β-catenin were quantified by Western blots...
July 2017: Molekuliarnaia Biologiia
https://www.readbyqxmd.com/read/28877210/tankyrase-inhibitors-suppress-hepatocellular-carcinoma-cell-growth-via-modulating-the-hippo-cascade
#6
Jiaoyuan Jia, Yu Qiao, Maria G Pilo, Antonio Cigliano, Xianqiong Liu, Zixuan Shao, Diego F Calvisi, Xin Chen
Previous data indicate that Tankyrase inhibitors exert anti-growth functions in many cancer cell lines due to their ability to inactivate the YAP protooncogene. In the present manuscript, we investigated the effect of Tankyrase inhibitors on the growth of hepatocellular carcinoma (HCC) cell lines and the molecular mechanisms involved. For this purpose, we performed cell proliferation assay by colony-forming ability in seven human HCC cells subjected to XAV-939 and G007-LK Tankyrase inhibitors. Noticeably, the two Tankyrase inhibitors suppressed the HCC cell growth in a dose-dependent manner...
2017: PloS One
https://www.readbyqxmd.com/read/28731148/molecular-genetics-and-targeted-therapy-of-wnt-related-human-diseases-review
#7
Masuko Katoh, Masaru Katoh
Canonical WNT signaling through Frizzled and LRP5/6 receptors is transduced to the WNT/β-catenin and WNT/stabilization of proteins (STOP) signaling cascades to regulate cell fate and proliferation, whereas non-canonical WNT signaling through Frizzled or ROR receptors is transduced to the WNT/planar cell polarity (PCP), WNT/G protein-coupled receptor (GPCR) and WNT/receptor tyrosine kinase (RTK) signaling cascades to regulate cytoskeletal dynamics and directional cell movement. WNT/β-catenin signaling cascade crosstalks with RTK/SRK and GPCR-cAMP-PKA signaling cascades to regulate β-catenin phosphorylation and β-catenin-dependent transcription...
September 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28723574/proteomic-analysis-of-the-human-tankyrase-protein-interaction-network-reveals-its-role-in-pexophagy
#8
Xu Li, Han Han, Mao-Tian Zhou, Bing Yang, Albert Paul Ta, Nan Li, Junjie Chen, Wenqi Wang
Tankyrase 1 (TNKS) and tankyrase 2 (TNKS2) belong to the poly(ADP-ribose) polymerase family of proteins, which use nicotinamide adenine dinucleotide to modify substrate proteins with ADP-ribose modifications. Emerging evidence has revealed the pathological relevance of TNKS and TNKS2, and identified these two enzymes as potential drug targets. However, the cellular functions and regulatory mechanisms of TNKS/2 are still largely unknown. Through a proteomic analysis, we defined the protein-protein interaction network for human TNKS/2 and revealed more than 100 high-confidence interacting proteins with numerous biological functions in this network...
July 18, 2017: Cell Reports
https://www.readbyqxmd.com/read/28695526/identifying-and-validating-tankyrase-binders-and-substrates-a-candidate-approach
#9
Katie Pollock, Michael Ranes, Ian Collins, Sebastian Guettler
The poly(ADP-ribose)polymerase (PARP) enzyme tankyrase (TNKS/ARTD5, TNKS2/ARTD6) uses its ankyrin repeat clusters (ARCs) to recognize degenerate peptide motifs in a wide range of proteins, thereby recruiting such proteins and their complexes for scaffolding and/or poly(ADP-ribosyl)ation. Here, we provide guidance for predicting putative tankyrase-binding motifs, based on the previously delineated peptide sequence rules and existing structural information. We present a general method for the expression and purification of tankyrase ARCs from Escherichia coli and outline a fluorescence polarization assay to quantitatively assess direct ARC-TBM peptide interactions...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28683851/survival-of-apc-mutant-colorectal-cancer-cells-requires-interaction-between-tankyrase-and-a-thiol-peroxidase-peroxiredoxin-ii
#10
Dong Hoon Kang, Joanna H S Lee, Sang Won Kang
Overexpression of mammalian 2-Cys peroxiredoxin (Prx) enzymes is observed in most cancer tissues. Nevertheless, their specific roles in colorectal cancer (CRC) progression has yet to be fully elucidated. Here, a novel molecular mechanism by which PrxII/Tankyrase (TNKS) interaction mediates survival of adenomatous polyposis coli (APC)-mutant CRC cells was explored. In mice with an inactivating APC mutation, a model of spontaneous intestinal tumorigenesis, deletion of PrxII reduced intestinal adenomatous polyposis and thereby increased survival...
August 2017: BMB Reports
https://www.readbyqxmd.com/read/28678390/small-molecules-inspired-by-the-natural-product-withanolides-as-potent-inhibitors-of-wnt-signaling
#11
Michael Sheremet, Shobhna Kapoor, Peter Schröder, Kamal Kumar, Slava Ziegler, Herbert Waldmann
Wnt signaling is a fundamental pathway that drives embryonic development and is essential for stem cell maintenance and tissue homeostasis. Dysregulation of Wnt signaling is linked to various diseases, and a constitutively active Wnt pathway drives tumorigenesis. Thus, disruption of the Wnt response is deemed a promising strategy for cancer drug discovery. However, only few clinical drug candidates that target Wnt signaling are available so far, and new small-molecule modulators of Wnt-related processes are in high demand...
September 19, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28659575/interaction-of-tankyrase-and-peroxiredoxin-ii-is-indispensable-for-the-survival-of-colorectal-cancer-cells
#12
Dong Hoon Kang, Doo Jae Lee, Sunmi Lee, So-Young Lee, Yukyung Jun, Yerin Kim, Youngeun Kim, Ju-Seog Lee, Dae-Kee Lee, Sanghyuk Lee, Eek-Hoon Jho, Dae-Yeul Yu, Sang Won Kang
Mammalian 2-Cys peroxiredoxin (Prx) enzymes are overexpressed in most cancer tissues, but their specific signaling role in cancer progression is poorly understood. Here we demonstrate that Prx type II (PrxII) plays a tumor-promoting role in colorectal cancer by interacting with a poly(ADP-ribose) polymerase (PARP) tankyrase. PrxII deletion in mice with inactivating mutation of adenomatous polyposis coli (APC) gene reduces intestinal adenomatous polyposis via Axin/β-catenin axis and thereby promotes survival...
June 28, 2017: Nature Communications
https://www.readbyqxmd.com/read/28628258/tankyrase-inhibition-regulates-corpus-luteum-development-and-luteal-function-in-gonadotropin-treated-rats
#13
Paula Accialini, Griselda Irusta, Andrés Bechis, Diana Bas, Fernanda Parborell, Dalhia Abramovich, Marta Tesone
Tankyrases are physiological regulators of Axin, a protein involved in several cellular processes, including Wnt signaling. Here, we investigated the effect of a specific Tankyrase inhibitor (XAV939) in follicular-luteal dynamics, and its possible relationship with ovarian vascular development. Studies were designed to analyze the effect of intrabursa administration of XAV939 in gonadotropin-treated prepubertal rats. In particular, we examined follicle and corpus luteum development, steroidogenesis, angiogenic markers, and apoptotic parameters...
August 2017: Molecular Reproduction and Development
https://www.readbyqxmd.com/read/28619731/usp25-regulates-wnt-signaling-by-controlling-the-stability-of-tankyrases
#14
Daichao Xu, Jianping Liu, Tao Fu, Bing Shan, Lihui Qian, Lifeng Pan, Junying Yuan
Aberrant activation of the Wnt signaling pathway plays an important role in human cancer development. Wnt signaling is negatively regulated by Axin, a scaffolding protein that controls a rate-limiting step in the destruction of β-catenin, the central activator of the Wnt pathway. In Wnt-stimulated cells, Axin is rapidly modified by tankyrase-mediated poly(ADP-ribosyl)ation, which promotes the proteolysis of Axin and consequent stabilization of β-catenin. Thus, regulation of the levels and activity of tankyrases is mechanistically important in controlling Wnt signaling...
May 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28615517/mtor-signaling-mediates-resistance-to-tankyrase-inhibitors-in-wnt-driven-colorectal-cancer
#15
Tetsuo Mashima, Yoko Taneda, Myung-Kyu Jang, Anna Mizutani, Yukiko Muramatsu, Haruka Yoshida, Ayana Sato, Noritaka Tanaka, Yoshikazu Sugimoto, Hiroyuki Seimiya
Activation of Wnt/β-catenin signaling is essential for colorectal carcinogenesis. Tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, is a positive regulator of the Wnt/β-catenin signaling. Accordingly, tankyrase inhibitors are under preclinical development for colorectal cancer (CRC) therapy. However, Wnt-driven colorectal cancer cells are not equally sensitive to tankyrase inhibitors, and cellular factors that affect tankyrase inhibitor sensitivity remain elusive. Here, we established a tankyrase inhibitor-resistant cell line, 320-IWR, from Wnt/β-catenin-dependent CRC COLO-320DM cells...
July 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28611108/wnt-%C3%AE-catenin-signaling-contributes-to-tumor-malignancy-and-is-targetable-in-gastrointestinal-stromal-tumor
#16
Shan Zeng, Adrian M Seifert, Jennifer Q Zhang, Michael J Cavnar, Teresa S Kim, Vinod P Balachandran, Juan A Santamaria-Barria, Noah A Cohen, Michael J Beckman, Benjamin D Medina, Ferdinand Rossi, Megan H Crawley, Jennifer K Loo, Joanna H Maltbaek, Peter Besmer, Cristina R Antonescu, Ronald P DeMatteo
Gastrointestinal stromal tumor (GIST) is the most common type of sarcoma and usually harbors either a KIT or PDGFRA mutation. However, the molecular basis for tumor malignancy is not well defined. Although the Wnt/β-catenin signaling pathway is important in a variety of cancers, its role in GIST is uncertain. Through analysis of nearly 150 human GIST specimens, we found that some human GISTs expressed β-catenin and contained active, dephosphorylated nuclear β-catenin. Furthermore, advanced human GISTs expressed reduced levels of the Wnt antagonist DKK4...
September 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28591512/discovery-of-a-highly-selective-tankyrase-inhibitor-displaying-growth-inhibition-effects-against-a-diverse-range-of-tumor-derived-cell-lines
#17
Douglas W Thomson, Anne J Wagner, Marcus Bantscheff, R Edward Benson, Lars Dittus, Birgit Duempelfeld, Gerard Drewes, Jana Krause, John T Moore, Katrin Mueller, Daniel Poeckel, Christina Rau, Elsa Salzer, Lisa Shewchuk, Carsten Hopf, John G Emery, Marcel Muelbaier
The availability of high quality probes for specific protein targets is fundamental to the investigation of their function and their validation as therapeutic targets. We report the utilization of a dedicated chemoproteomic assay platform combining affinity enrichment technology with high-resolution protein mass spectrometry to the discovery of a novel nicotinamide isoster, the tetrazoloquinoxaline 41, a highly potent and selective tankyrase inhibitor. We also describe the use of 41 to investigate the biology of tankyrase, revealing the compound induced growth inhibition of a number of tumor derived cell lines, demonstrating the potential of tankyrase inhibitors in oncology...
July 13, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28588489/fh535-suppresses-osteosarcoma-growth-in-vitro-and-inhibits-wnt-signaling-through-tankyrases
#18
Carl T Gustafson, Tewodros Mamo, Kristen L Shogren, Avudaiappan Maran, Michael J Yaszemski
Osteosarcoma (OS) is an aggressive primary bone tumor which exhibits aberrantly activated Wnt signaling. The canonical Wnt signaling cascade has been shown to drive cancer progression and metastasis through the activation of β-catenin. Hence, small molecule inhibitors of Wnt targets are being explored as primary or adjuvant chemotherapy. In this study, we have investigated the ability of FH535, an antagonist of Wnt signaling, to inhibit the growth of OS cells. We found that FH535 was cytotoxic in all OS cell lines which were tested (143b, U2OS, SaOS-2, HOS, K7M2) but well tolerated by normal human osteoblast cells...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28371398/targeting-tankyrase-to-fight-wnt-dependent-tumours
#19
REVIEW
Tor Espen Thorvaldsen
Aberrant WNT signalling activity is linked to various diseases due to the WNT dependency of fundamental processes during development and in adult tissue homeostasis. Mutations in components of the multi-protein β-catenin destruction complex promote excessive amounts of the main transcriptional activator β-catenin and are particularly common in colorectal cancer (CRC). The tankyrase enzymes were recently implicated as negative regulators of destruction complex activity by mediating degradation of the scaffolding protein AXIN...
April 2, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28337959/microrna-940-targets-inpp4a-or-gsk3%C3%AE-and-activates-the-wnt-%C3%AE-catenin-pathway-to-regulate-the-malignant-behavior-of-bladder-cancer-cells
#20
Rong Wang, Yunfeng Wu, Weihua Huang, Weijun Chen
We aimed to explore the roles and regulatory mechanism of microRNA-940 (miR-940) in bladder cancer development. The expressions of miR-940 in bladder cancer tissues and cells were measured. Then miR-940 mimics, miR-940 inhibitor mall interference RNA against INPP4A (si-INPP4A) and GSK3β (si-GSK3β) and their corresponding controls were transfected into cells. We then investigated that the effects of miR-940, INPP4A or GSK3β on cell proliferation, migration, invasion and apoptosis. Additionally, target prediction and luciferase reporter assay were performed to investigate the targets of miR-940...
March 23, 2017: Oncology Research
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