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https://www.readbyqxmd.com/read/28340172/repositioning-disulfiram-as-a-radiosensitizer-against-atypical-teratoid-rhabdoid-tumor
#1
Young Eun Lee, Seung Ah Choi, Pil Ae Kwack, Hak Jae Kim, Il Han Kim, Kyu-Chang Wang, Ji Hoon Phi, Ji Yeoun Lee, Sangjoon Chong, Sung-Hye Park, Kyung Duk Park, Do Won Hwang, Kyeung Min Joo, Seung-Ki Kim
Background.: Atypical teratoid/rhabdoid tumor (AT/RT) is one of the most common malignant brain tumors in infants. Although cancer stem cells of AT/RT express aldehyde dehydrogenase (ALDH), effective chemotherapies against AT/RT have not been established. Here, we examined radiosensitizing effects of disulfiram (DSF), an irreversible inhibitor of ALDH against AT/RT for a novel therapeutic method. Methods.: Patient-derived primary cultured AT/RT cells (SNU.AT/RT-5 and SNU...
March 17, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28331416/dna-pk-inhibition-by-nu7441-enhances-chemosensitivity-to-topoisomerase-inhibitor-in-non-small-cell-lung-carcinoma-cells-by-blocking-dna-damage-repair
#2
Masaaki Yanai, Haruhiko Makino, Bingqiong Ping, Kenichi Takeda, Natsumi Tanaka, Tomohiro Sakamoto, Kosuke Yamaguchi, Masahiro Kodani, Akira Yamasaki, Tadashi Igishi, Eiji Shimizu
BACKGROUND: DNA double-strand breaks (DSBs) are the most cytotoxic form of DNA damage and are induced by ionizing radiation and specific chemotherapeutic agents, such as topoisomerase inhibitors. Cancer cells acquire resistance to such therapies by repairing DNA DSBs. A major pathway for the repair of DNA DSBs is non-homologous end-joining (NHEJ), which requires DNA-dependent protein kinase (DNA-PK) activity. In this study, we investigated the effect of NU7441, a synthetic small-molecule compound, as a specific inhibitor of DNA-PK on the chemosensitization of non-small cell lung carcinoma (NSCLC) A549 cells...
March 2017: Yonago Acta Medica
https://www.readbyqxmd.com/read/28329681/sirt6-promotes-dna-end-joining-in-ipscs-derived-from-old-mice
#3
Wen Chen, Nana Liu, Hongxia Zhang, Haiping Zhang, Jing Qiao, Wenwen Jia, Songcheng Zhu, Zhiyong Mao, Jiuhong Kang
Induced pluripotent stem cells (iPSCs) have great potential for treating age-related diseases, but the genome integrity of iPSCs is critically important. Here, we demonstrate that non-homologous end joining (NHEJ), rather than homologous recombination (HR), is less efficient in iPSCs from old mice than young mice. We further find that Sirt6 is downregulated in iPSCs from old mice. Sirt6 directly binds to Ku80 and facilitates the Ku80/DNA-PKcs interaction, thus promoting DNA-PKcs phosphorylation at residue S2056, leading to efficient NHEJ...
March 21, 2017: Cell Reports
https://www.readbyqxmd.com/read/28328082/microrna-488-3p-sensitizes-malignant-melanoma-cells-to-cisplatin-by-targeting-prkdc
#4
Ning Li, Yue Ma, Li Ma, Yu Guan, Liang Ma, Daping Yang
Deregulation of microRNAs (miRNAs) has been implicated in drug resistance in various types of cancers, including malignant melanoma (MM). MiR-488-3p has been reported as a tumor suppressor in several cancers. However, the exact expression patterns of miR-488-3p and the precise molecular mechanisms underlying its role in MM remain largely unknown and require further investigation. In this study, we demonstrated that miR-488-3p is significantly down regulated in MM clinical specimens and cell lines. Ectopic expression of miR-488-3p resulted in markedly increased drug sensitivity of MM cells in vitro and in vivo...
March 22, 2017: Cell Biology International
https://www.readbyqxmd.com/read/28315428/p53-modulates-the-effect-of-ribosomal-protein-s6-kinase1-s6k1-on-cisplatin-toxicity-in-chronic-myeloid-leukemia-cells
#5
Ling-Yi Xiao, Wai-Ming Kan
Chronic myeloid leukemia (CML) is characterized by the expression of the oncoprotein, BCR-ABL. BCR-ABL inhibitors revolutionized CML chemotherapy while blast crisis (BC) CML patients are less responsive. Since suppression of ribosomal protein S6 kinase1 (S6K1) phosphorylation reverses the resistance to BCR-ABL inhibitor in CML cells and S6K1 inhibitors augment cisplatin toxicity in lung cancer cells, we speculated that combination of S6K1 inhibitor and cisplatin may be beneficial for eliminating BC CML cells...
March 14, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28300555/inhibiting-dna-pkcs-radiosensitizes-human-osteosarcoma-cells
#6
Tewodros Mamo, Ann C Mladek, Kris L Shogren, Carl Gustafson, Shiv K Gupta, Scott M Riester, Avudaiappan Maran, Mario Galindo, Andre J van Wijnen, Jann N Sarkaria, Michael J Yaszemski
Osteosarcoma survival rate has not improved over the past three decades, and the debilitating side effects of the surgical treatment suggest the need for alternative local control approaches. Radiotherapy is largely ineffective in osteosarcoma, indicating a potential role for radiosensitizers. Blocking DNA repair, particularly by inhibiting the catalytic subunit of DNA-dependent protein kinase (DNA-PKCS), is an attractive option for the radiosensitization of osteosarcoma. In this study, the expression of DNA-PKCS in osteosarcoma tissue specimens and cell lines was examined...
March 11, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28270495/the-checkpoint-kinase-1-inhibitor-prexasertib-induces-regression-of-preclinical-models-of-human-neuroblastoma
#7
Caitlin D Lowery, Alle B VanWye, Michele Dowless, Wayne Blosser, Beverly L Falcon, Julie Stewart, Jennifer Stephens, Richard P Beckmann, Aimee Bence Lin, Louis F Stancato
PURPOSE: Checkpoint kinase 1 (CHK1) is a key regulator of the DNA damage response and a mediator of replication stress through modulation of replication fork licensing and activation of S and G2/M cell cycle checkpoints. We evaluated prexasertib (LY2606368), a small molecule CHK1 inhibitor currently in clinical testing, in multiple preclinical models of pediatric cancer. Following an initial assessment of prexasertib activity, this study focused on preclinical models of neuroblastoma...
March 7, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28258841/stimulation-of-lactate-receptor-hcar1-affects-cellular-dna-repair-capacity
#8
Waldemar Wagner, Katarzyna D Kania, Wojciech M Ciszewski
Numerous G-protein coupled receptors have been reported to enhance cancer cell survival and resistance to clinically used chemotherapeutics. Recently, hydroxycarboxylic acid receptor 1 (HCAR1) was shown to drive lactate-dependent enhancement of cell survival and metastasis in pancreatic and breast cancers. Furthermore, our previous study confirmed the involvement of HCAR1 in lactate-related enhancement of DNA repair in cervical cancer cells. In the present study, we examined the possible mechanisms of HCAR1-mediated enhancement of DNA repair capacity...
February 20, 2017: DNA Repair
https://www.readbyqxmd.com/read/28254786/clinical-impact-of-tumor-dna-repair-expression-and-t-cell-infiltration-in-breast-cancers
#9
Andrew R Green, Mohammed A Aleskandarany, Reem Ali, Eleanor Grace Hodgson, Suha Atabani, Karen De Souza, Emad Rakha, Ian O Ellis, Srinivasan Madhusudan
Impaired DNA repair drives mutagenicity, which increases neoantigen load and immunogenicity. We investigated the expression of proteins involved in the DNA damage response (ATM, Chk2), double-strand break repair (BRCA1, BLM, WRN, RECQL4, RECQL5, TOPO2A, DNA-PKcs, Ku70/Ku80), nucleotide excision repair (ERCC1), base excision repair (XRCC1, pol β, FEN1, PARP1), and immune responses (CD8, PD-1, PD-L1, FOXP3) in 1269 breast cancers and validated our findings in an independent estrogen receptor (ER)- cohort (n = 279)...
March 2, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28224663/loss-of-mlh1-sensitizes-colon-cancer-cells-to-dna-pkcs-inhibitor-ku60648
#10
Inga Hinrichsen, Anne Ackermann, Tonja Düding, Annika Graband, Natalie Filmann, Guido Plotz, Stefan Zeuzem, Angela Brieger
Germline mutations of MLH1 are responsible for tumor generation in nearly 50% of patients with Lynch Syndrome, and around 15% of sporadic colorectal cancers show MLH1-deficiency due to promotor hypermethylation. Although these tumors are of lower aggressiveness the benefit for these patients from standard chemotherapy is still under discussion. Recently, it was shown that the sensitivity to the DNA-PKcs inhibitor KU60648 is linked to loss of the MMR protein MSH3. However, loss of MSH3 is rather secondary, as a consequence of MMR-deficiency, and frequently detectable in MLH1-deficient tumors...
February 22, 2017: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/28209968/activating-akt1-mutations-alter-dna-double-strand-break-repair-and-radiosensitivity
#11
S Oeck, K Al-Refae, H Riffkin, G Wiel, R Handrick, D Klein, G Iliakis, V Jendrossek
The survival kinase Akt has clinical relevance to radioresistance. However, its contributions to the DNA damage response, DNA double strand break (DSB) repair and apoptosis remain poorly defined and often contradictory. We used a genetic approach to explore the consequences of genetic alterations of Akt1 for the cellular radiation response. While two activation-associated mutants with prominent nuclear access, the phospho-mimicking Akt1-TDSD and the clinically relevant PH-domain mutation Akt1-E17K, accelerated DSB repair and improved survival of irradiated Tramp-C1 murine prostate cancer cells and Akt1-knockout murine embryonic fibroblasts in vitro, the classical constitutively active membrane-targeted myrAkt1 mutant had the opposite effects...
February 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28193772/the-dna-pkcs-structure-suggests-dsb-repair-is-allosterically-regulated
#12
(no author information available yet)
The structure of DNA-PKcs in complex with KU80 suggests KU80 promotes allosteric activation of DNA-PKcs.
February 13, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28187004/didymin-an-orally-active-citrus-flavonoid-for-targeting-neuroblastoma
#13
REVIEW
Sharad S Singhal, Sulabh Singhal, Preeti Singhal, Jyotsana Singhal, David Horne, Sanjay Awasthi
Neuroblastoma, a rapidly growing yet treatment responsive cancer, is the third most common cancer of children and the most common solid tumor in infants. Unfortunately, neuroblastoma that has lost p53 function often has a highly treatment-resistant phenotype leading to tragic outcomes. In the context of neuroblastoma, the functions of p53 and MYCN (which is amplified in ~25% of neuroblastomas) are integrally linked because they are mutually transcriptionally regulated, and because they together regulate the catalytic activity of RNA polymerases...
February 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28186989/inhibiting-dna-pkcs-in-a-non-homologous-end-joining-pathway-in-response-to-dna-double-strand-breaks
#14
Jun Dong, Tian Zhang, Yufeng Ren, Zhenyu Wang, Clifton C Ling, Fuqiu He, Gloria C Li, Chengtao Wang, Bixiu Wen
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a distinct factor in the non-homologous end-joining (NHEJ) pathway involved in DNA double-strand break (DSB) repair. We examined the crosstalk between key proteins in the DSB NHEJ repair pathway and cell cycle regulation and found that mouse embryonic fibroblast (MEF) cells deficient in DNA-PKcs or Ku70 were more vulnerable to ionizing radiation (IR) compared with wild-type cells and that DSB repair was delayed. γH2AX was associated with phospho-Ataxia-telangiectasia mutated kinase (Ser1987) and phospho-checkpoint effector kinase 1 (Ser345) foci for the arrest of cell cycle through the G2/M phase...
February 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28179558/cell-specific-pkm-isoforms-contribute-to-the-maintenance-of-different-forms-of-persistent-long-term-synaptic-plasticity
#15
Jiangyuan Hu, Kerry Adler, Carole Abi Farah, Margaret H Hastings, Wayne S Sossin, Samuel Schacher
Multiple kinase activations contribute to long-term synaptic plasticity, a cellular mechanism mediating long-term memory. The sensorimotor synapse of Aplysia expresses different forms of long-term facilitation (LTF)-nonassociative and associative LTF-that require the timely activation of kinases, including protein kinase C (PKC). It is not known which PKC isoforms in the sensory neuron or motor neuron L7 are required to sustain each form of LTF. We show that different PKMs, the constitutively active isoforms of PKCs generated by calpain cleavage, in the sensory neuron and L7 are required to maintain each form of LTF...
March 8, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28155885/regulation-of-pairing-between-broken-dna-containing-chromatin-regions-by-ku80-dna-pkcs-atm-and-53bp1
#16
Motohiro Yamauchi, Atsushi Shibata, Keiji Suzuki, Masatoshi Suzuki, Atsuko Niimi, Hisayoshi Kondo, Miwa Miura, Miyako Hirakawa, Keiko Tsujita, Shunichi Yamashita, Naoki Matsuda
Chromosome rearrangement is clinically and physiologically important because it can produce oncogenic fusion genes. Chromosome rearrangement requires DNA double-strand breaks (DSBs) at two genomic locations and misrejoining between the DSBs. Before DSB misrejoining, two DSB-containing chromatin regions move and pair with each other; however, the molecular mechanism underlying this process is largely unknown. We performed a spatiotemporal analysis of ionizing radiation-induced foci of p53-binding protein 1 (53BP1), a marker for DSB-containing chromatin...
February 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28154854/nanospray-hx-ms-configuration-for-structural-interrogation-of-large-protein-systems
#17
Joey G Sheff, Morgan Hepburn, Yaping Yu, Susan P Lees-Miller, David C Schriemer
Hydrogen-deuterium exchange mass spectrometry (HX-MS) has made important contributions to the study of protein structure and function. Unfortunately, it is not known for low limits of detection, when compared with other forms of peptide-based or bottom-up protein MS methods. Systems perform poorly on sub-pmol quantities of protein states with greater than 300 kDa of unique sequences. The HX-MS analysis of complex protein states would be possible if proteomics-grade configurations could be used reliably, but temperature and temporal constraints have proven to be significant design challenges...
March 13, 2017: Analyst
https://www.readbyqxmd.com/read/28154079/dna-pkcs-structure-suggests-an-allosteric-mechanism-modulating-dna-double-strand-break-repair
#18
Bancinyane L Sibanda, Dimitri Y Chirgadze, David B Ascher, Tom L Blundell
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a central component of nonhomologous end joining (NHEJ), repairing DNA double-strand breaks that would otherwise lead to apoptosis or cancer. We have solved its structure in complex with the C-terminal peptide of Ku80 at 4.3 angstrom resolution using x-ray crystallography. We show that the 4128-amino acid structure comprises three large structural units: the N-terminal unit, the Circular Cradle, and the Head. Conformational differences between the two molecules in the asymmetric unit are correlated with changes in accessibility of the kinase active site, which are consistent with an allosteric mechanism to bring about kinase activation...
February 3, 2017: Science
https://www.readbyqxmd.com/read/28133776/non-homologous-end-joining-common-interaction-sites-and-exchange-of-multiple-factors-in-the-dna-repair-process
#19
Stuart L Rulten, Gabrielle J Grundy
Non-homologous end-joining (NHEJ) is the dominant means of repairing chromosomal DNA double strand breaks (DSBs), and is essential in human cells. Fifteen or more proteins can be involved in the detection, signalling, synapsis, end-processing and ligation events required to repair a DSB, and must be assembled in the confined space around the DNA ends. We review here a number of interaction points between the core NHEJ components (Ku70, Ku80, DNA-PKcs, XRCC4 and Ligase IV) and accessory factors such as kinases, phosphatases, polymerases and structural proteins...
March 2017: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/28131528/expression-of-dna-damage-response-proteins-in-cervical-cancer-patients-treated-with-radical-chemoradiotherapy
#20
C K Ho, E N Kornaga, A C Klimowicz, E K Enwere, M Dean, G D Bebb, T Phan, P Ghatage, A M Magliocco, S P Lees-Miller, C M Doll
OBJECTIVE: The management of locally advanced cervical cancer has improved significantly with the advent of cisplatin-based chemoradiotherapy (CRT) as the primary treatment regimen. Nevertheless, a significant proportion of patients fail to respond or relapse on this treatment and have a very poor prognosis. Our goal was to determine the prognostic value of a panel of proteins involved in detection and repair of DNA damage. METHODS: We performed fluorescence immunohistochemistry, and used software analysis to assess expression of DNA damage response proteins ATM, DNA-PKcs, PARP-1, Ku70 and Ku86 in 117 pre-treatment specimens from patients with locally advanced cervical cancer...
January 25, 2017: Gynecologic Oncology
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