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Luka Horvat, Mariastefania Antica, Maja Matulić
Differentiation of blood cells is one of the most complex processes in the body. It is regulated by the action of transcription factors in time and space which creates a specific signaling network. In the hematopoietic signaling system, Notch is one of the main regulators of lymphocyte development. The aim of this study was to get insight into the regulation of Notch signalization and the influence of poly(ADP-ribose)polymerase (PARP) activity on this process in three leukemia cell lines obtained from B and T cells...
June 14, 2018: Cells
Manuel Schlimpert, Simon Lagies, Vadym Budnyk, Barbara Müller, Gerd Walz, Bernd Kammerer
Nephronophthisis (NPH) is an autosomal recessive form of cystic kidney disease and the leading cause of hereditary kidney failure in children and young adults. Like other NPH proteins, the NPHP16/Anks6-interacting protein Anks3 has been identified to cause laterality defects in humans. However, the cellular functions of Anks3 remain enigmatic. We investigated the metabolic impact of Anks3 depletion in cultured murine inner medullary collecting duct cells via GC-MS profiling and LC-MS/MS analysis. Combined metabolomics successfully identified 155 metabolites; 48 metabolites were identified to be significantly altered by decreasing Anks3 levels...
June 13, 2018: Scientific Reports
Katherine Sullivan-Reed, Elisabeth Bolton-Gillespie, Yashodhara Dasgupta, Samantha Langer, Micheal Siciliano, Margaret Nieborowska-Skorska, Kritika Hanamshet, Elizaveta A Belyaeva, Andrea J Bernhardy, Jaewong Lee, Morgan Moore, Huaqing Zhao, Peter Valent, Ksenia Matlawska-Wasowska, Markus Müschen, Smita Bhatia, Ravi Bhatia, Neil Johnson, Mariusz A Wasik, Alexander V Mazin, Tomasz Skorski
PARP inhibitors (PARPis) have been used to induce synthetic lethality in BRCA-deficient tumors in clinical trials with limited success. We hypothesized that RAD52-mediated DNA repair remains active in PARPi-treated BRCA-deficient tumor cells and that targeting RAD52 should enhance the synthetic lethal effect of PARPi. We show that RAD52 inhibitors (RAD52is) attenuated single-strand annealing (SSA) and residual homologous recombination (HR) in BRCA-deficient cells. Simultaneous targeting of PARP1 and RAD52 with inhibitors or dominant-negative mutants caused synergistic accumulation of DSBs and eradication of BRCA-deficient but not BRCA-proficient tumor cells...
June 12, 2018: Cell Reports
Ewa Gogola, Alexandra A Duarte, Julian R de Ruiter, Wouter W Wiegant, Jonas A Schmid, Roebi de Bruijn, Dominic I James, Sergi Guerrero Llobet, Daniel J Vis, Stefano Annunziato, Bram van den Broek, Marco Barazas, Ariena Kersbergen, Marieke van de Ven, Madalena Tarsounas, Donald J Ogilvie, Marcel van Vugt, Lodewyk F A Wessels, Jirina Bartkova, Irina Gromova, Miguel Andújar-Sánchez, Jiri Bartek, Massimo Lopes, Haico van Attikum, Piet Borst, Jos Jonkers, Sven Rottenberg
Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, drug resistance is a clinical hurdle, and we poorly understand how cancer cells escape the deadly effects of PARPi without restoring the HR pathway. By combining genetic screens with multi-omics analysis of matched PARPi-sensitive and -resistant Brca2-mutated mouse mammary tumors, we identified loss of PAR glycohydrolase (PARG) as a major resistance mechanism...
June 11, 2018: Cancer Cell
Julita Pietrzak, Corinne M Spickett, Tomasz Płoszaj, László Virág, Agnieszka Robaszkiewicz
Although electrophiles are considered as detrimental to cells, accumulating recent evidence indicates that proliferating non-cancerous and particularly cancerous cells utilize these agents for pro-survival and cell cycle promoting signaling. Hence, the redox shift to mild oxidant release must be balanced by multiple defense mechanisms. Our latest findings demonstrate that cell cycle progression, which dictates oxidant level in stress-free conditions, determines PARP1 transcription. Growth modulating factors regulate CDK4/6-RBs-E2Fs axis...
June 2, 2018: Redox Biology
Farhadul Islam, Vinod Gopalan, Alfred K-Y Lam, Syed Rashel Kabir
Globally, colorectal cancer is the third most common type of malignant tumor, after lung and breast. Here anticancer property of pea lectin was evaluated against colorectal cancer cell lines SW480 and SW48. The cells were treated with different doses of lectin for 3 days in vitro and the inhibitory effects were found in a dose dependent manner. At the high dose(1.0 mg/ml) 62% and 63% cell growth inhibitions were observed for SW48 and SW480 cell lines, respectively. Cell growth inhibition was further studied by colony formation of the cell lines and the numbers of colonies in SW480+pea lectin and SW48+pea lectin cells were noted significantly lower in comparison to that of control cells...
June 6, 2018: International Journal of Biological Macromolecules
Anuratha Sakthianandeswaren, Marie Parsons, Dmitri Mouradov, Ruth N MacKinnon, Bruno Catimel, Sheng Liu, Michelle Palmieri, Christopher G Love, Robert N Jorissen, Shan Li, Lachlan Whitehead, Tracy L Putoczki, Adele Preaudet, Cary Tsui, Cameron J Nowell, Robyn L Ward, Nicholas J Hawkins, Jayesh Desai, Peter Gibbs, Matthias Ernst, Ian Street, Michael Buchert, Oliver M Sieber
ADP-ribosylation is an important post-translational protein modification that regulates diverse biological processes, controlled by dedicated transferases and hydrolases. Here we show that frequent deletions (~30%) of the MACROD2 mono-ADP-ribosylhydrolase locus in human colorectal cancer (CRC) cause impaired PARP1 transferase activity in a gene dosage-dependent manner. MACROD2 haploinsufficiency alters DNA repair and sensitivity to DNA damage, and results in chromosome instability. Heterozygous and homozygous depletion of Macrod2 enhances intestinal tumorigenesis in ApcMin/+ mice and the growth of human CRC xenografts...
June 7, 2018: Cancer Discovery
Saeed Nazari Soltan Ahmad, Nadereh Rashtchizadeh, Hassan Argani, Leila Roshangar, Amir Ghorbani Haghjo, Davoud Sanajou, Fatemeh Panah, Zahra Ashrafi Jigheh, Siavoush Dastmalchi, Mehran Mesgari-Abbasi
Despite being an efficacious anticancer agent, the clinical utility of cisplatin is hindered by its cardinal side effects. This investigation aimed to appraise potential protective impact of dunnione, a natural naphthoquinone pigment with established NQO1 stimulatory effects, on cisplatin nephrotoxicity of rats. Dunnione was administered orally at 10 and 20 mg/kg doses for 4 d and a single injection of cisplatin was delivered at the second day. Renal histopathology, inflammatory/oxidative stress/apoptotic markers, kidney function, and urinary markers of renal injury were assessed...
June 4, 2018: Free Radical Research
Nikolaos Tsoukalas, Eleni Aravantinou-Fatorou, Panagiotis Baxevanos, Maria Tolia, Konstantinos Tsapakidis, Michail Galanopoulos, Michail Liontos, George Kyrgias
Small cell lung cancer (SCLC) remains one of the most lethal malignancies and a major health riddle. The therapeutic options are limited. The combination of etoposide or irinotecan with platinum chemotherapy is the standard of care at any stage. The last decade systemic efforts have been done to reveal specific therapeutic targets for small cell lung carcinomas. In this review, we focus on the new therapeutic strategies of SCLC, including immune-related treatment that may change the prognosis of the disease...
April 2018: Annals of Translational Medicine
Jake Jianjun Wen, Yuhui Whitney Yin, Nisha Jain Garg
Chagasic cardiomyopathy is caused by Trypanosoma cruzi infection. Poly(ADP-ribose) polymerase 1 (PARP1) is known for its function in nuclear DNA repair. In this study, we have employed genetic deletion and chemical inhibition approaches to determine the role of PARP1 in maintaining mtDNA dependent mitochondrial function in Chagas disease. Our data show that expression of PARP1 and protein PARylation were increased by >2-fold and >16-fold, respectively, in the cytosolic, nuclear, and mitochondrial fractions of the human cardiac myocytes and the myocardium of wildtype (WT) mice chronically infected with T...
May 2018: PLoS Pathogens
Zhiming Li, Yinglu Li, Ming Tang, Bin Peng, Xiaopeng Lu, Qiaoyan Yang, Qian Zhu, Tianyun Hou, Meiting Li, Chaohua Liu, Lina Wang, Xingzhi Xu, Ying Zhao, Haiying Wang, Yang Yang, Wei-Guo Zhu
Linker histone H1 is a master regulator of higher order chromatin structure, but its involvement in the DNA damage response and repair is unclear. Here, we report that linker histone H1.2 is an essential regulator of ataxia telangiectasia mutated (ATM) activation. We show that H1.2 protects chromatin from aberrant ATM activation through direct interaction with the ATM HEAT repeat domain and inhibition of MRE11-RAD50-NBS1 (MRN) complex-dependent ATM recruitment. Upon DNA damage, H1.2 undergoes rapid PARP1-dependent chromatin dissociation through poly-ADP-ribosylation (PARylation) of its C terminus and further proteasomal degradation...
May 29, 2018: Cell Research
Qing Liu, Dongchuan Zhu, Baozhen Hao, Zhiwei Zhang, Yongjie Tian
Luteolin (LUT) is a flavone universally presented in plants. It shows an anti-carcinogenic effect in different cancers and could increase the sensitivity of cisplatin in colorectal cancer cell lines through Nrf2 pathway. However, the effect of luteolin on the sensitivity to ovarian cancer cells has not been studied. In this study, luteolin was found to suppress autophagy with reduced expression of LC3-II, but enhanced the inhibition of cell vitality and promoted apoptosis induced by cisplatin, leading to restoration of the sensitivity to cisplatin in ovarian cancer cells through CCK-8, flow cytometry and immunofluorescent assays...
May 15, 2018: Cellular and Molecular Biology
Elizaveta E Alemasova, Konstantin N Naumenko, Tatyana A Kurgina, Rashid O Anarbaev, Olga I Lavrik
Y-box-binding protein 1 (YB-1) is a multifunctional cellular factor overexpressed in tumors resistant to chemotherapy. An intrinsically disordered structure together with a high positive charge peculiar to YB-1 allows this protein to function in almost all cellular events related to nucleic acids including RNA, DNA and poly(ADP-ribose) (PAR). In the present study we show that YB-1 acts as a potent poly(ADP-ribose) polymerase 1 (PARP1) cofactor that can reduce the efficiency of PARP1 inhibitors. Similarly to that of histones or polyamines, stimulatory effect of YB-1 on the activity of PARP1 was significantly higher than the activator potential of Mg2+ and was independent of the presence of EDTA...
May 4, 2018: Oncotarget
Zhi-Liang Jin, Wei Yan, Mei Qu, Chang-Zheng Ge, Xia Chen, Shao-Feng Zhang
Cinchonine is a natural compound present in Cinchona bark. It exerts multidrug resistance reversal activity and synergistic apoptotic effect with paclitaxel in uterine sarcoma cells. Whether cinchonine is effective against human liver cancer, however, remains elusive. A total of five liver cancer cell lines including Bel-7402, MHCC97H, HepG2, Hep3B and SMCC7721 were used. The anti-proliferative effects of cinchonine on these liver cancer cell lines were assessed by MTT assay. The apoptotic effects of cinchonine on liver cancer cell lines were assessed by flow cytometry with Annexin V/propidium iodide assay...
June 2018: Experimental and Therapeutic Medicine
Ana M Hurtado, Gines Luengo-Gil, Tzu H Chen-Liang, Fabio Amaral, Kiran Batta, Laura Palomo, Eva Lumbreras, Bartlomiej Przychodzen, Eva Caparros, Marıa L Amigo, Maria Dıez-Campelo, Lurdes Zamora, Eduardo J Salido Fierrez, Jaroslaw P Maciejewski, Francisco J Ortuño, Vicente Vicente, Marıa Del Canizo, Francesc Sole, Francisca Ferrer-Marin, Daniel H Wiseman, Andres Jerez
Despite the absence of mutations in the DNA repair machinery in myeloid malignancies, the advent of high-throughput sequencing and discovery of splicing and epigenetics defects in chronic myelomonocytic leukaemia (CMML) prompted us to revisit a pathogenic role for genes involved in DNA damage response. We screened for misregulated DNA repair genes by enhanced RNA-sequencing on bone marrow from a discovery cohort of 27 CMML patients and 9 controls. We validated 4 differentially expressed candidates in CMML CD34+ bone marrow selected cells and in an independent cohort of 74 CMML patients, mutationally contextualized by targeted sequencing, and assessed their transcriptional behavior in 70 myelodysplastic syndrome, 66 acute myeloid leukaemia and 25 chronic myeloid leukaemia cases...
May 24, 2018: British Journal of Haematology
Ruoxi Wang, Chunshuang Li, Ping Qiao, Yaoyao Xue, Xu Zheng, Hongyu Chen, Xianlu Zeng, Wenguang Liu, Istvan Boldogh, Xueqing Ba
Oxidative stress-induced DNA damage has been well acknowledged as a major cause leading to cell death, which is etiologically linked to ischemic injury and degenerative alterations. The most common oxidation product of DNA is base lesion 8-oxo-7,8-dihydroguanine (8-oxoG), which is repaired by 8-oxoG glycosylase1 (OGG1)-initiated baseexcision repair (BER) pathway (OGG1-BER); however, the role of OGG1-BER in oxidative stress-induced cell death is poorly investigated. DNA strand breaks and apurinic/apyrimidinic (AP) sites are effective substrates to activate DNA damage sensor poly(ADP-ribose) polymerase 1 (PARP1)...
May 24, 2018: Cell Death & Disease
Silvia Maifrede, Margaret Nieborowska-Skorska, Katherine Sullivan, Yashodhara Dasgupta, Paulina Podszywalow-Bartnicka, Bac Viet Le, Martyna Solecka, Zhaorui Lian, Elizaveta A Belyaeva, Alina Nersesyan, Marcin M Machnicki, Monika Toma, Nicolas Chatain, Malgorzata Rydzanicz, Huaqing Zhao, Jaroslav Jelinek, Katarzyna Piwocka, Tomasz Sliwinski, Tomasz Stoklosa, Rafal Ploski, Thomas Fischer, Stephen M Sykes, Steffen Koschmieder, Lars Bullinger, Peter Valent, Mariusz Wasik, Jian Huang, Tomasz Skorski
Mutations in the FMS-like tyrosine-kinase 3 (FLT3) such as internal tandem duplications (ITD) can be found in up to 23% of patients with acute myeloid leukemia (AML) and confer a poor prognosis. Current treatment options for FLT3(ITD)-positive AMLs include genotoxic therapy and FLT3 inhibitors (FLT3i), which are rarely curative. PARP1 inhibitors (PARP1i) have been successfully applied to induce synthetic lethality in tumors harboring BRCA1/2 mutations and displaying homologous recombination (HR) deficiency...
May 21, 2018: Blood
Hye Jeong Park, Jun Sang Bae, Kyoung Min Kim, Young Jae Moon, See-Hyoung Park, Sang Hoon Ha, Usama Khamis Hussein, Zhongkai Zhang, Ho Sung Park, Byung-Hyun Park, Woo Sung Moon, Jung Ryul Kim, Kyu Yun Jang
BACKGROUND: PARP1 facilitates the recovery of DNA-damaged cells by recruiting DNA damage response molecules such as γH2AX and BRCA1/2, and plays a role in resistance to antitumor therapies. Therefore, PARP inhibition being evaluated as an anti-cancer therapy. However, there are limited studies regrading PARP inhibition in osteosarcoma. METHODS: We evaluated the expression of DNA damage response molecules in 35 human osteosarcomas and investigated the effects of co-treatment of the PARP inhibitor, olaparib, and doxorubicin in osteosarcoma cells...
May 21, 2018: Journal of Experimental & Clinical Cancer Research: CR
Xiangbing Meng, Jianling Bi, Yujun Li, Shujie Yang, Yuping Zhang, Mary Li, Haitao Liu, Yiyang Li, Megan E Mcdonald, Kristina W Thiel, Kuo-Kuang Wen, Xinhao Wang, Meng Wu, Kimberly K Leslie
Tumor suppressor p53 is responsible for enforcing cell cycle checkpoints at G1/S and G2/M in response to DNA damage, thereby allowing both normal and tumor cells to repair DNA before entering S and M. However, tumor cells with absent or mutated p53 are able to activate alternative signaling pathways that maintain the G2/M checkpoint, which becomes uniquely critical for the survival of such tumor cells. We hypothesized that abrogation of the G2 checkpoint might preferentially sensitize p53-defective tumor cells to DNA-damaging agents and spare normal cells with intact p53 function...
May 19, 2018: Cancers
Heqiang Qi, Yuyan Lu, Jie Lv, Huita Wu, Jing Lu, Changmao Zhang, Sheng Zhang, Qing Bao, Xiuming Zhang, Chengrong Xie, Zhenyu Yin
Hepatocellular carcinoma (HCC) accounts for a large proportion of cancer-associated mortality worldwide. The functional impact of long noncoding RNAs (lncRNAs) in human cancer is not fully understood. Here, we identified a novel oncogenic lncRNA termed lncPARP1, which was significantly upregulated in HCC. Increase of lncPARP1 expression was associated with age, AFP levels, tumor size, recurrence, and poor prognosis of HCC patients. Loss-of-function approaches showed that knockdown of lncPARP1 inhibited proliferation, migration and invasion, while induced apoptosis in HCC cells...
May 18, 2018: Bioscience Reports
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