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https://www.readbyqxmd.com/read/29669812/tankyrase-modulates-insulin-sensitivity-in-skeletal-muscle-cells-by-regulating-the-stability-of-glut4-vesicle-proteins
#1
Zhiduan Su, Vinita Deshpande, David E James, Jacqueline Stöckli
Tankyrase1 and 2, members of the poly(ADP-ribose) polymerase family, have previously been shown to play a role in insulin-mediated glucose uptake in adipocytes. However, their precise mechanism of action, and their role in insulin action in other cell types, such as myocytes, remains elusive. Treatment of differentiated L6 myotubes with the small molecule tankyrase inhibitor XAV939 resulted in insulin resistance as determined by impaired insulin-stimulated glucose uptake. Proteomic analysis of XAV939-treated myotubes identified down-regulation of several glucose transporter GLUT4 storage vesicle (GSV) proteins including RAB10, VAMP8, SORT1 and GLUT4...
April 18, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29605737/rucaparib-an-emerging-parp-inhibitor-for-treatment-of-recurrent-ovarian-cancer
#2
REVIEW
Angela Musella, Erlisa Bardhi, Claudia Marchetti, Laura Vertechy, Giusy Santangelo, Carolina Sassu, Federica Tomao, Francesco Rech, Renzo D'Amelio, Marco Monti, Innocenza Palaia, Ludovico Muzii, Pierluigi Benedetti Panici
Recently, Poly-ADP-Ribose Polymerase (PARP) inhibitors are one of the most intensively studied group of antiblastic agents for the management of recurrent ovarian cancer. Among this family, Olaparib was the first to be approved by European Medicines Agency as maintenance therapy post-response to platinum-based chemotherapy for recurrent ovarian cancer in women with deleterious BRCA1/2 mutation. Following that, the Food and Drug Administration (FDA) approved Olaparib monotherapy as fourth or later line of treatment in advanced ovarian cancer with deleterious germ-line BRCA1/2 mutation...
March 23, 2018: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/29604130/structural-basis-for-tankyrase-rnf146-interaction-reveals-noncanonical-tankyrase-binding-motifs
#3
Paul A DaRosa, Rachel E Klevit, Wenqing Xu
Poly(ADP-ribosyl)ation (PARylation) catalyzed by the tankyrase enzymes (Tankyrase-1 and -2; a.k.a. PARP-5a and -5b) is involved in mitosis, telomere length regulation, GLUT-4 vesicle transport, and cell growth and differentiation. Together with the E3 ubiquitin ligase RNF146 (a.k.a. Iduna), tankyrases regulate the cellular concentrations of several important proteins including Axin, 3BP2, and angiomotins, which are key regulators of Wnt, Src and hippo signaling, respectively. These substrates of tankyrases are first PARylated and then ubiquitylated by RNF146, which is allosterically activated by binding to PAR polymer...
March 31, 2018: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/29593045/degradation-of-a-novel-dna-damage-response-protein-tankyrase-1-binding-protein-1-tab182-following-adenovirus-infection
#4
Nafiseh Chalabi Hagkarim, Ellis L Ryan, Philip J Byrd, Robert Hollingworth, Neil J Shimwell, Angelo Agathanggelou, Manon Vavasseur, Viktoria Kolbe, Thomas Speiseder, Thomas Dobner, Grant S Stewart, Roger J Grand
Infection by most DNA viruses activates a cellular DNA damage response (DDR), which may be to the detriment or advantage of the virus. In the case of adenoviruses, they neutralise anti-viral effects of DDR activation by targeting a number of proteins for rapid proteasome-mediated degradation. We have now identified a novel DDR protein, tankyrase 1 binding protein 1 (TNKS1BP1 also known as Tab182), which is degraded during infection by adenovirus 5 and adenovirus 12. In both cases, degradation requires the action of E1B55K and E4orf6 viral proteins and is mediated through the proteasome by the action of cullin-based cellular E3 ligases...
March 28, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29556050/versatile-protein-recognition-by-the-encoded-display-of-multiple-chemical-elements-on-a-constant-macrocyclic-scaffold
#5
Yizhou Li, Roberto De Luca, Samuele Cazzamalli, Francesca Pretto, Davor Bajic, Jörg Scheuermann, Dario Neri
In nature, specific antibodies can be generated as a result of an adaptive selection and expansion of lymphocytes with suitable protein binding properties. We attempted to mimic antibody-antigen recognition by displaying multiple chemical diversity elements on a defined macrocyclic scaffold. Encoding of the displayed combinations was achieved using distinctive DNA tags, resulting in a library size of 35,393,112. Specific binders could be isolated against a variety of proteins, including carbonic anhydrase IX, horseradish peroxidase, tankyrase 1, human serum albumin, alpha-1 acid glycoprotein, calmodulin, prostate-specific antigen and tumour necrosis factor...
April 2018: Nature Chemistry
https://www.readbyqxmd.com/read/29491053/combination-treatment-of-polo-like-kinase-1-and-tankyrase-1-inhibitors-enhances-anticancer-effect-in-triple-negative-breast-cancer-cells
#6
Geun-Hyoung Ha, Dong-Young Kim, Eun-Kyoung Breuer, Chung Kwon Kim
BACKGROUND/AIM: Breast cancer is the most common malignant cancer type in women, and triple-negative breast cancer (TNBC) is an extremely aggressive subtype of breast cancer with poor prognosis rates. The present study investigated the antitumor effect of polo-like kinase 1 (PLK1) inhibitor in combination with the tankyrase-1 (TNKS1) inhibitor on TNBC cells. MATERIALS AND METHODS: We evaluated the antitumor effects of combination therapy with PLK1 and TNKS1 inhibitor using cell viability analysis, apoptosis assay and transwell assay for cell invasion and migration in TNBC cells...
March 2018: Anticancer Research
https://www.readbyqxmd.com/read/29412166/efflux-inhibition-by-iwr-1-endo-confers-sensitivity-to-doxorubicin-effects-in-osteosarcoma-cells
#7
Carl T Gustafson, Tewodros Mamo, Avudaiappan Maran, Michael J Yaszemski
Osteosarcoma is the most common bone tumor that affects children and young adults. Despite advances in the use of combination chemotherapy regimens, response to neoadjuvant chemotherapy in osteosarcoma remains a key determinant of patient outcome. Recently, highly potent small molecule inhibitors of canonical Wnt signaling through the poly(ADP-ribose) polymerase (PARP)-family enzymes, tankyrases 1 & 2 (Tnks1/2), have been considered as possible chemotherapy sensitizing agents. The goal of this study was to determine the ability of the highly specific Tnks1/2 inhibitor IWR-1-endo to sensitize chemotherapy-resistant osteosarcoma to doxorubicin...
February 2, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29374194/2-phenylquinazolinones-as-dual-activity-tankyrase-kinase-inhibitors
#8
Yves Nkizinkiko, Jenny Desantis, Jarkko Koivunen, Teemu Haikarainen, Sudarshan Murthy, Luca Sancineto, Serena Massari, Federica Ianni, Ezeogo Obaji, Maria I Loza, Taina Pihlajaniemi, Jose Brea, Oriana Tabarrini, Lari Lehtiö
Tankyrases (TNKSs) are enzymes specialized in catalyzing poly-ADP-ribosylation of target proteins. Several studies have validated TNKSs as anti-cancer drug targets due to their regulatory role in Wnt/β-catenin pathway. Recently a lot of effort has been put into developing more potent and selective TNKS inhibitors and optimizing them towards anti-cancer agents. We noticed that some 2-phenylquinazolinones (2-PQs) reported as CDK9 inhibitors were similar to previously published TNKS inhibitors. In this study, we profiled this series of 2-PQs against TNKS and selected kinases that are involved in the Wnt/β-catenin pathway...
January 26, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29348564/inhibition-of-wnt-%C3%AE-catenin-signaling-under-serum-starvation-and-hypoxia-induces-adipocytic-transdifferentiation-in-human-leiomyoma-cells
#9
Hiroshi Harada, Yojiro Tsuda, Kei Yabuki, Eisuke Shiba, Kazuyoshi Uchihashi, Atsuji Matsuyama, Yoshihisa Fujino, Toru Hachisuga, Masanori Hisaoka
Fatty metamorphosis is an uncommon alteration in uterine leiomyoma (i.e., lipoleiomyoma), and the pathogenetic mechanisms underlying this phenomenon remain poorly understood. Because a conditional deletion of β-catenin, a major transducer of the canonical Wingless/integrated (WNT) pathway, in the developing mouse uterus can induce adipogenesis in the myometrium, it is hypothesized that inhibition of the WNT/β-catenin signaling may be also involved in the development of fat cells within uterine leiomyoma. In the current study, which was performed to address this point, intracytoplasmic lipid droplets were detectable in cultured human leiomyoma cells by treatment with a potent tankyrase inhibitor, XAV939, which antagonizes β-catenin, in a serum-starved culture medium without additional adipogenesis-inducing agents or supplements, and showed increasing accumulation in a time-dependent manner...
January 18, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29344117/wnt-inhibitor-xav939-suppresses-the-viability-of-small-cell-lung-cancer-nci-h446-cells-and-induces-apoptosis
#10
Wenxuan Guo, Fangzhen Shen, Wenjing Xiao, Jing Chen, Fei Pan
Small cell lung cancer (SCLC) is the most aggressive type of lung cancer due to a fast tumor doubling time and early hematogenous spread. Advances in the treatment of non-small cell lung cancer using targeted therapies having been made, but no targeted drugs for SCLC have been approved. The Wnt signaling pathway is associated with tumor progression and metastasis; therefore, the inhibition of Wnt/β-catenin signaling is a strategy for anticancer drugs. Tankyrase 1 (TNKS1) is overexpressed in a number of types of cancer and XAV939 is a small molecule inhibitor of TNKS1 which may inhibit tumor growth...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29316982/the-tankyrase-inhibitor-g007-lk-inhibits-small-intestine-lgr5-stem-cell-proliferation-without-altering-tissue-morphology
#11
Jens Henrik Norum, Ellen Skarpen, Andreas Brech, Raoul Kuiper, Jo Waaler, Stefan Krauss, Therese Sørlie
BACKGROUND: The WNT pathway regulates intestinal stem cells and is frequently disrupted in intestinal adenomas. The pathway contains several potential biotargets for interference, including the poly-ADP ribosyltransferase enzymes tankyrase1 and 2. LGR5 is a known WNT pathway target gene and marker of intestinal stem cells. The LGR5+ stem cells are located in the crypt base and capable of regenerating all intestinal epithelial cell lineages. RESULTS: We treated Lgr5-EGFP-Ires-CreERT2;R26R-Confetti mice with the tankyrase inhibitor G007-LK for up to 3 weeks to assess the effect on duodenal stem cell homeostasis and on the integrity of intestinal epithelium...
January 9, 2018: Biological Research
https://www.readbyqxmd.com/read/29250169/therapeutic-strategies-against-cancer-stem-cells-in-human-colorectal-cancer
#12
Magdalena Szaryńska, Agata Olejniczak, Jarosław Kobiela, Piotr Spychalski, Zbigniew Kmieć
Colorectal cancer (CRC) is the third most frequent malignancy and represents the fourth most common cause of cancer-associated mortalities in the world. Despite many advances in the treatment of CRC, the 5-year survival rate of patients with CRC remains unsatisfactory due to tumor recurrence and metastases. Recently, cancer stem cells (CSCs), have been suggested to be responsible for the initiation and relapse of the disease, and have been identified in CRC. Due to their basic biological features, which include self-renewal and pluripotency, CSCs may be novel therapeutic targets for CRC and other cancer types...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29222171/tankyrase-inhibition-enhances-the-antiproliferative-effect-of-pi3k-and-egfr-inhibition-mutually-affecting-%C3%AE-catenin-and-akt-signaling-in-colorectal-cancer
#13
Nina T Solberg, Jo Waaler, Kaja Lund, Line Mygland, Petter A Olsen, Stefan Krauss
Overactivation of the WNT/β-CATENIN signaling axis is a common denominator in colorectal cancer. Currently, there is no available WNT inhibitor in clinical practice. Although TANKYRASE (TNKS) inhibitors have been proposed as promising candidates, there are many colorectal cancer models that do not respond positively to TNKS inhibition in vitro and in vivo Therefore, a combinatorial therapeutic approach combining a TNKS inhibitor (G007-LK) with PI3K (BKM120) and EGFR (erlotinib) inhibitors in colorectal cancer was investigated...
March 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29179156/radiosensitization-with-an-inhibitor-of-poly-adp-ribose-glycohydrolase-a-comparison-with-the-parp1-2-3-inhibitor-olaparib
#14
Polly Gravells, James Neale, Emma Grant, Amit Nathubhai, Kate M Smith, Dominic I James, Helen E Bryant
Upon DNA binding the poly(ADP-ribose) polymerase family of enzymes (PARPs) add multiple ADP-ribose subunits to themselves and other acceptor proteins. Inhibitors of PARPs have become an exciting and real prospect for monotherapy and as sensitizers to ionising radiation (IR). The action of PARPs are reversed by poly(ADP-ribose) glycohydrolase (PARG). Until recently studies of PARG have been limited by the lack of an inhibitor. Here, a first in class, specific, and cell permeable PARG inhibitor, PDD00017273, is shown to radiosensitize...
January 2018: DNA Repair
https://www.readbyqxmd.com/read/29168093/application-of-two-dimensional-binary-fingerprinting-methods-for-the-design-of-selective-tankyrase-i-inhibitors
#15
B S Muddukrishna, Vasudev Pai, Richard Lobo, Aravinda Pai
In the present study, five important binary fingerprinting techniques were used to model novel flavones for the selective inhibition of Tankyrase I. From the fingerprints used: the fingerprint atom pairs resulted in a statistically significant 2D QSAR model using a kernel-based partial least square regression method. This model indicates that the presence of electron-donating groups positively contributes to activity, whereas the presence of electron withdrawing groups negatively contributes to activity. This model could be used to develop more potent as well as selective analogues for the inhibition of Tankyrase I...
November 22, 2017: Molecular Diversity
https://www.readbyqxmd.com/read/29155568/discovery-of-a-novel-series-of-tankyrase-inhibitors-by-a-hybridization-approach
#16
Upendra Rao Anumala, Jo Waaler, Yves Nkizinkiko, Alexander Ignatev, Katina Lazarow, Peter Lindemann, Petter Angell Olsen, Sudarshan Murthy, Ezeogo Obaji, Alexander G Majouga, Sergey Leonov, Jens Peter von Kries, Lari Lehtiö, Stefan Krauss, Marc Nazaré
A structure-guided hybridization approach using two privileged substructures gave instant access to a new series of tankyrase inhibitors. The identified inhibitor 16 displays high target affinity on tankyrase 1 and 2 with biochemical and cellular IC50 values of 29 nM, 6.3 nM and 19 nM, respectively, and high selectivity toward other poly (ADP-ribose) polymerase enzymes. The identified inhibitor shows a favorable in vitro ADME profile as well as good oral bioavailability in mice, rats, and dogs. Critical for the approach was the utilization of an appropriate linker between 1,2,4-triazole and benzimidazolone moieties, whereby a cyclobutyl linker displayed superior affinity compared to a cyclohexane and phenyl linker...
December 28, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29126913/iwr-1-a-tankyrase-inhibitor-attenuates-wnt-%C3%AE-catenin-signaling-in-cancer-stem-like-cells-and-inhibits-in-vivo-the-growth-of-a-subcutaneous-human-osteosarcoma-xenograft
#17
Sara R Martins-Neves, Daniela I Paiva-Oliveira, Carlos Fontes-Ribeiro, Judith V M G Bovée, Anne-Marie Cleton-Jansen, Célia M F Gomes
Wnt/β-catenin or canonical Wnt signaling pathway regulates the self-renewal of cancer stem-like cells (CSCs) and is involved in tumor progression and chemotherapy resistance. Previously, we reported that this pathway is activated in a subset of osteosarcoma CSCs and that doxorubicin induced stemness properties in differentiated cells through Wnt/β-catenin activation. Here, we investigated whether pharmacological Wnt/β-catenin inhibition, using a tankyrase inhibitor (IWR-1), might constitute a strategy to target CSCs and improve chemotherapy efficacy in osteosarcoma...
February 1, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29107427/targeting-wnt-driven-cancers-discovery-of-novel-tankyrase-inhibitors
#18
REVIEW
Martina Ferri, Paride Liscio, Andrea Carotti, Stefania Asciutti, Roccaldo Sardella, Antonio Macchiarulo, Emidio Camaioni
Recent years have seen substantially heightened interest in the discovery of tankyrase inhibitors (TNKSi) as new promising anticancer agents. In this framework, the aim of this review article is focused on the description of potent TNKSi also endowed with disruptor activity toward the Wnt/β-catenin signaling pathway. Beginning with an overview of the most characterized TNKSi deriving from several drug design approaches and classifying them on the basis of the molecular interactions with the target, we discuss only those ones acting against Wnt cancer cell lines...
December 15, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29055830/pharmacological-inhibition-of-tankyrase-induces-bone-loss-in-mice-by-increasing-osteoclastogenesis
#19
Shunichi Fujita, Tomoyuki Mukai, Takafumi Mito, Shoko Kodama, Akiko Nagasu, Mizuho Kittaka, Teruki Sone, Yasuyoshi Ueki, Yoshitaka Morita
Tankyrase is a poly (ADP-ribose) polymerase that leads to ubiquitination and degradation of target proteins. Since tankyrase inhibitors suppress the degradation of AXIN protein, a negative regulator of the canonical Wnt pathway, they effectively act as Wnt inhibitors. Small molecule tankyrase inhibitors are being investigated as drug candidates for cancer and fibrotic diseases, in which the Wnt pathways are aberrantly activated. Tankyrase is also reported to degrade the adaptor protein SH3BP2 (SH3 domain-binding protein 2)...
October 18, 2017: Bone
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
#20
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)...
November 2017: International Journal of Oncology
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