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Dna damage and cancer

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https://www.readbyqxmd.com/read/28934364/the-histone-variant-macroh2a-confers-functional-robustness-to-the-intestinal-stem-cell-compartment
#1
Ryan James Cedeno, Angela Nakauka-Ddamba, Maryam Yousefi, Stephanie Sterling, Nicolae Adrian Leu, Ning Li, John R Pehrson, Christopher Joachim Lengner
A stem cell's epigenome directs cell fate during development, homeostasis, and regeneration. Epigenetic dysregulation can lead to inappropriate cell fate decisions, aberrant cell function, and even cancer. The histone variant macroH2A has been shown to influence gene expression, guide cell fate, and safeguard against genotoxic stress. Interestingly, mice lacking functional macroH2A histones (hereafter referred to as macroH2A DKO) are viable and fertile; yet suffer from increased perinatal death and reduced weight and size compared to wildtype (WT)...
2017: PloS One
https://www.readbyqxmd.com/read/28934154/why-human-papillomaviruses-activate-the-dna-damage-response-ddr-and-how-cellular-and-viral-replication-persists-in-the-presence-of-ddr-signaling
#2
REVIEW
Molly L Bristol, Dipon Das, Iain M Morgan
Human papillomaviruses (HPV) require the activation of the DNA damage response (DDR) in order to undergo a successful life cycle. This activation presents a challenge for the virus and the infected cell: how does viral and host replication proceed in the presence of a DDR that ordinarily arrests replication; and how do HPV16 infected cells retain the ability to proliferate in the presence of a DDR that ordinarily arrests the cell cycle? This raises a further question: why do HPV activate the DDR? The answers to these questions are only partially understood; a full understanding could identify novel therapeutic strategies to target HPV cancers...
September 21, 2017: Viruses
https://www.readbyqxmd.com/read/28933366/the-role-of-the-mapk-signaling-topoisomerase-and-dietary-bioactives-in-controlling-cancer-incidence
#3
REVIEW
Khaled A Selim, Hend Abdelrasoul, Mohamed Aboelmagd, Ahmed M Tawila
Reactive oxygen species (ROS) are common products of mitochondrial oxidative phosphorylation, xenobiotics metabolism and are generated in response to several environmental stress conditions. Some of them play important biochemical roles in cellular signal transduction and gene transcription. On the other hand, ROS are known to be involved in a wide range of human diseases, including cancer. The excessive production of such ROS together with disruption of homeostasis detoxifying mechanisms can mediate a series of cellular oxidative stresses...
April 26, 2017: Diseases (Basel)
https://www.readbyqxmd.com/read/28933263/anticancer-properties-of-a-new-hybrid-analog-ad-013-combining-a-coumarin-scaffold-with-an-%C3%AE-methylene-%C3%AE-lactone-motif
#4
Angelika Długosz, Katarzyna Gach-Janczak, Jacek Szymański, Dariusz Deredas, Henryk Krawczyk, Tomasz Janecki, Anna Janecka
Background Coumarin is a natural phytochemical but as such has no medical uses. However, various natural and synthetic coumarin analogs attract attention due to their interesting biological properties. </P><P> Objective Here, we evaluated and compared anticancer properties of a new synthetic hybrid compound AD-013, which integrates a coumarin moiety and an α-methylene-δ-lactone motif, with novobiocin, a natural antibiotic bearing a coumarin scaffold. </P><P> Method Cytotoxic activities of compound AD-013 and novobiocin were assessed by the MTT assay...
September 21, 2017: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28931330/sequential-molecular-changes-and-dynamic-oxidative-stress-in-high-grade-serous-ovarian-carcinogenesis
#5
Hiroshi Kobayashi, Kenji Ogawa, Naoki Kawahara, Kana Iwai, Emiko Niiro, Sachiko Morioka, Yuki Yamada
The mechanism of high-grade serous ovarian cancer (HGSC) development remains elusive. This review outlines recent advances in the understanding of sequential molecular changes associated with the development of HGSC, as well as describes oxidative stress-induced genomic instability and carcinogenesis. This article reviews the English-language literature between 2005 and 2017. Clinicopathological features analysis provide a sequential progression of fallopian tubal epithelium to precursor lesions to type 2 HGSC...
September 21, 2017: Free Radical Research
https://www.readbyqxmd.com/read/28930680/systematic-kinase-inhibitor-profiling-identifies-cdk9-as-a-synthetic-lethal-target-in-nut-midline-carcinoma
#6
Johannes Brägelmann, Marcel A Dammert, Felix Dietlein, Johannes M Heuckmann, Axel Choidas, Stefanie Böhm, André Richters, Debjit Basu, Verena Tischler, Carina Lorenz, Peter Habenberger, Zhizhou Fang, Sandra Ortiz-Cuaran, Frauke Leenders, Jan Eickhoff, Uwe Koch, Matthäus Getlik, Martin Termathe, Muhammad Sallouh, Zoltán Greff, Zoltán Varga, Hyatt Balke-Want, Christopher A French, Martin Peifer, H Christian Reinhardt, László Örfi, György Kéri, Sascha Ansén, Lukas C Heukamp, Reinhard Büttner, Daniel Rauh, Bert M Klebl, Roman K Thomas, Martin L Sos
Kinase inhibitors represent the backbone of targeted cancer therapy, yet only a limited number of oncogenic drivers are directly druggable. By interrogating the activity of 1,505 kinase inhibitors, we found that BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells are specifically killed by CDK9 inhibition (CDK9i) and depend on CDK9 and Cyclin-T1 expression. We show that CDK9i leads to robust induction of apoptosis and of markers of DNA damage response in NMC cells. While both CDK9i and bromodomain inhibition over time result in reduced Myc protein expression, only bromodomain inhibition induces cell differentiation and a p21-induced cell-cycle arrest in these cells...
September 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/28929116/the-diagnostic-value-of-nuclear-matrix-proteins-in-bladder-cancer-in-the-aspect-of-environmental-risk-from-carcinogens
#7
Beata Szymańska, Ewa Sawicka, Anna Guzik, Romuald Zdrojowy, Anna Długosz
BACKGROUND: The interaction of environmental factors with genetic susceptibility and detoxification level seems to be an important causative factor in bladder cancer (BC). The aim of this study was to look for a BC marker panel which reflects the environmental risk. The nuclear matrix protein 22 (NMP22), bladder cancer-4 (BLCA-4), and total level proteins NMP22 and BLCA-4 (NMBL) in BC patients with genetic predisposition NAT2 (classified as slow acetylators, SA), DNA damage (8-OHdG), and detoxification by isoenzyme GSTπ activity were measured...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28927115/wee1-inhibition-by-mk1775-as-a-single-agent-therapy-inhibits-ovarian-cancer-viability
#8
Minghui Zhang, Donye Dominguez, Siqi Chen, Jie Fan, Lei Qin, Alan Long, Xia Li, Yi Zhang, Huirong Shi, Bin Zhang
Wee1-like protein kinase (WEE1) physiologically serves a key function in maintaining the integrity of the cell genome through mediating the activation of cyclin-dependent kinase (CDK)1 and CDK2. Increased expression of WEE1 has been associated with the poor prognosis of patients with ovarian cancer. The present study aimed at examining the in vitro and in vivo antitumor activity of MK1775, a potent pharmacological inhibitor of WEE1, as a single agent against ovarian cancer cells. The cytotoxicity of MK1775 was examined in a panel of tumor cells using MTT in vitro...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28927105/reactive-oxygen-species-driven-mitochondrial-injury-induces-apoptosis-by-teroxirone-in-human-non-small-cell-lung-cancer-cells
#9
Jing-Ping Wang, Chang-Heng Hsieh, Chun-Yen Liu, Kai-Han Lin, Pei-Tsun Wu, Kwun-Min Chen, Kang Fang
Teroxirone as an anticancer agent is used to treat human lung cancer by inducing apoptotic cell death. Previous studies have demonstrated that the status of the tumor suppressor p53 determined the onset of apoptotic cell death in human non-small cell lung cancer cells (NSCLC). In order to further understand the underlying mechanisms of lung cancer, the present study explored the targets of teroxirone. By including antioxidants, the present study analyzed changes in cell proliferation, cell cycle division, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), expression of apoptosis markers and cytochrome c distribution...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28926637/selective-cytotoxicity-of-the-anti-diabetic-drug-metformin-in-glucose-deprived-chicken-dt40-cells
#10
Kei Kadoda, Takahito Moriwaki, Masataka Tsuda, Hiroyuki Sasanuma, Masamichi Ishiai, Minoru Takata, Hiroshi Ide, Shin-Ichiro Masunaga, Shunichi Takeda, Keizo Tano
Metformin is a biguanide drug that is widely used in the treatment of diabetes. Epidemiological studies have indicated that metformin exhibits anti-cancer activity. However, the molecular mechanisms underlying this activity currently remain unclear. We hypothesized that metformin is cytotoxic in a tumor-specific environment such as glucose deprivation and/or low oxygen (O2) tension. We herein demonstrated that metformin was highly cytotoxic under glucose-depleted, but not hypoxic (2% O2) conditions. In order to elucidate the underlying mechanisms of this selective cytotoxicity, we treated exposed DNA repair-deficient chicken DT40 cells with metformin under glucose-depleted conditions and measured cellular sensitivity...
2017: PloS One
https://www.readbyqxmd.com/read/28926421/a-novel-hydroxyphenyl-hydrazone-derivate-ycl0426-inhibits-cancer-cell-proliferation-through-sequestering-iron
#11
Feifei Li, Long Long, Junhai Xiao, Chen Wang, Wei Li, Song Li, Changqi Zhao, Lili Wang
Cancer cells have an increased requirement for iron than normal cells, and iron chelators are under active consideration for cancer treatment. The metal-sequestering potential and antiproliferative mechanisms of a novel hydroxyphenyl hydrazone derivate YCL0426 were investigated here. Antiproliferative activity of YCL0426 was detected by MTT assay. The iron-sequestering potential was evaluated by ferrozine-Fe(II) sequestering assay and Fe(II) titration assay. Cell-cycle-arresting profile was checked by flow cytometry and the DNA synthesis status was evaluated by BrdU incorporation assay...
September 18, 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/28925391/ezh2-contributes-to-the-response-to-parp-inhibitors-through-its-parp-mediated-poly-adp-ribosylation-in-breast-cancer
#12
H Yamaguchi, Y Du, K Nakai, M Ding, S-S Chang, J L Hsu, J Yao, Y Wei, L Nie, S Jiao, W-C Chang, C-H Chen, Y Yu, G N Hortobagyi, M-C Hung
Inhibitors against poly (ADP-ribose) polymerase (PARP) are promising targeted agents currently used to treat BRCA-mutant ovarian cancer and are in clinical trials for other cancer types, including BRCA-mutant breast cancer. To enhance the clinical response to PARP inhibitors (PARPis), understanding the mechanisms underlying PARPi sensitivity is urgently needed. Here, we show enhancer of zeste homolog 2 (EZH2), an enzyme that catalyzes H3 lysine trimethylation and associates with oncogenic function, contributes to PARPi sensitivity in breast cancer cells...
September 18, 2017: Oncogene
https://www.readbyqxmd.com/read/28924389/structural-maintenance-of-chromosomes-protein-1-role-in-genome-stability-and-tumorigenesis
#13
REVIEW
Fei Yi, Zhuo Wang, Jingwei Liu, Ying Zhang, Zhijun Wang, Hongde Xu, Xiaoman Li, Ning Bai, Liu Cao, Xiaoyu Song
SMC1 (Structural Maintenance of Chromosomes protein 1), well known as one of the SMC superfamily members, has been explored to function in many activities including chromosome dynamics, cell cycle checkpoint, DNA damage repair and genome stability. Upon being properly assembled as part of cohesin, SMC1 can be phosphorylated by ATM and mediate downstream DNA damage repair after ionizing irradiation. Abnormal gene expression or mutation of SMC1 can cause defect in the DNA damage repair pathway, which has been strongly associated with tumorigenesis...
2017: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/28923836/dna-pk-plays-a-central-role-in-transformation-of-breast-epithelial-cells-following-alkylation-damage
#14
Libi Anandi, Vaishali Chakravarty, K A Ashiq, Satish Bodakuntla, Mayurika Lahiri
DNA alkylating agents form the first line of cancer chemotherapy. They not only kill cells but also behave as potential carcinogens. MNU, a DNA methylating agent is well known to induce mammary tumours in rodents. However, the mechanism of tumorigenesis is not well understood. Our study reports a novel role played by DNA-PK in methylation damage-induced transformation using three dimensional breast acinar cultures. Here, we report that exposure of breast epithelial cells to MNU led to their inhibition to polarise at the basolateral domain, increased dispersal of Golgi at the apical domain, induction of EMT-like phenotype as well as invasion...
September 18, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28923379/synthesis-characterization-cellular-uptake-and-apoptosis-inducing-properties-of-two-highly-cytotoxic-cyclometalated-ruthenium-ii-%C3%AE-carboline-complexes
#15
Jincan Chen, Fa Peng, Yao Zhang, Baojun Li, Ji She, Xinming Jie, Zhilin Zou, Man Chen, Lanmei Chen
Two new cyclometalated Ru(II) complexes of the general formula [Ru(N-N)2(1-Ph-βC)](PF6), where N-N = 4,4'-dimethyl-2,2'-bipyridine (dmb, Ru1), 2,2'-bipyridine (bpy, Ru2), and 1-Ph-βC (1-phenyl-9H-pyrido[3,4-b]indole) is a β-carboline alkaloids derivatives, have been synthesized and characterized. The in vitro cytotoxicities, cellular uptake and localization, cell cycle arrest and apoptosis-inducing mechanisms of these complexes have been extensively explored by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, inductively coupled plasma mass spectrometry (ICP-MS), flow cytometry, comet assay, inverted fluorescence microscope as well as western blotting experimental techniques...
September 6, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28922417/lingering-single-strand-breaks-trigger-rad51-independent-homology-directed-repair-of-collapsed-replication-forks-in-the-polynucleotide-kinase-phosphatase-mutant-of-fission-yeast
#16
Arancha Sanchez, Mariana C Gadaleta, Oliver Limbo, Paul Russell
The DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) protects genome integrity by restoring ligatable 5'-phosphate and 3'-hydroxyl termini at single-strand breaks (SSBs). In humans, PNKP mutations underlie the neurological disease known as MCSZ, but these individuals are not predisposed for cancer, implying effective alternative repair pathways in dividing cells. Homology-directed repair (HDR) of collapsed replication forks was proposed to repair SSBs in PNKP-deficient cells, but the critical HDR protein Rad51 is not required in PNKP-null (pnk1Δ) cells of Schizosaccharomyces pombe...
September 18, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28921800/initial-testing-stage-1-of-m6620-formerly-vx-970-a-novel-atr-inhibitor-alone-and-combined-with-cisplatin-and-melphalan-by-the-pediatric-preclinical-testing-program
#17
Raushan T Kurmasheva, Dias Kurmashev, C Patrick Reynolds, Min Kang, Jianwrong Wu, Peter J Houghton, Malcolm A Smith
BACKGROUND: M6620 is a novel inhibitor of the DNA damage repair enzyme ATR, and has potentiated the activity of cisplatin and irinotecan in non-small cell lung cancer and colon cancer xenografts, respectively. PROCEDURES: M6620 was tested in vitro at concentrations ranging from 1.0 nM to 10.0 μM and at 75 nM in combination with cisplatin or melphalan. M6620 was tested against 24 solid tumor xenografts alone and in combination with cisplatin. Cisplatin was administered intraperitoneally on days 1 and 8 at a dose of 5 mg/kg...
September 17, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28920955/mir-25-93-mediates-hypoxia-induced-immunosuppression-by-repressing-cgas
#18
Min-Zu Wu, Wei-Chung Cheng, Su-Feng Chen, Shin Nieh, Carolyn O'Connor, Chia-Lin Liu, Wen-Wei Tsai, Cheng-Jang Wu, Lorena Martin, Yaoh-Shiang Lin, Kou-Juey Wu, Li-Fan Lu, Juan Carlos Izpisua Belmonte
The mechanisms by which hypoxic tumours evade immunological pressure and anti-tumour immunity remain elusive. Here, we report that two hypoxia-responsive microRNAs, miR-25 and miR-93, are important for establishing an immunosuppressive tumour microenvironment by downregulating expression of the DNA sensor cGAS. Mechanistically, miR-25/93 targets NCOA3, an epigenetic factor that maintains basal levels of cGAS expression, leading to repression of cGAS during hypoxia. This allows hypoxic tumour cells to escape immunological responses induced by damage-associated molecular pattern molecules, specifically the release of mitochondrial DNA...
September 18, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28918914/analysis-of-genomes-and-transcriptomes-of-hepatocellular-carcinomas-identifies-mutations-and-gene-expression-changes-in-the-transforming-growth-factor-beta-pathway-short-title-prognostic-significance-of-tgf-%C3%AE-signature-in-liver-cancer
#19
Jian Chen, Sobia Zaidi, Shuyun Rao, Jiun-Sheng Chen, Liem Phan, Patrizia Farci, Xiaoping Su, Kirti Shetty, Jon White, Fausto Zamboni, Xifeng Wu, Asif Rashid, Nagarajan Pattabiraman, Raja Mazumder, Anelia Horvath, Ray-Chang Wu, Shulin Li, Cuiying Xiao, Chu-Xia Deng, David A Wheeler, Bibhuti Mishra, Rehan Akbani, Lopa Mishra
BACKGROUND & AIMS: Development of hepatocellular carcinoma (HCC) is associated with alterations in the transforming growth factor beta (TGFβ) signaling pathway, which regulates liver inflammation and can have tumor suppressor or promoter activities. Little is known about the roles of specific members of this pathway at specific of HCC development. We took an integrated approach to identify and validate the effects of changes in this pathway in HCC and identify therapeutic targets. METHODS: We performed transcriptome analyses for a total of 488 HCCs that include data from The Cancer Genome Atlas...
September 14, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28918707/wdnfinder-a-method-for-minimum-driver-node-set-detection-and-analysis-in-directed-and-weighted-biological-network
#20
Chu Yanshuo, Wang Zhenxing, Wang Rongjie, Zhang Ningyi, Li Jie, Hu Yang, Teng Mingxiang, Wang Yadong
Structural controllability is the generalization of traditional controllability for dynamical systems. During the last decade, interesting biological discoveries have been inferred by applied structural controllability analysis to biological networks. However, false positive/negative information (i.e. nodes and edges) widely exists in biological networks that documented in public data sources, which can hinder accurate analysis of structural controllability. In this study, we propose WDNfinder, a comprehensive analysis package that provides structural controllability with consideration of node connection strength in biological networks...
September 4, 2017: Journal of Bioinformatics and Computational Biology
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