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https://www.readbyqxmd.com/read/28927087/gimeracil-enhances-the-antitumor-effect-of-cisplatin-in-oral-squamous-cell-carcinoma-cells-in-vitro-and-in-vivo
#1
Koji Harada, Tarannum Ferdous, Toyoko Harada, Takanori Takenawa, Yoshiya Ueyama
Gimeracil or 5-chloro-2,4-dihydroxypyridine (CDHP) enhances the antitumor effects of 5-fluorouracil (5-FU) by inhibiting dihydropyrimidine dehydrogenase (DPD), which is involved in the degradation of 5-FU. CDHP, as part of a combination therapy, was also reported to exert a radiosensitizing effect. Therefore, CDHP may have underlying mechanisms of action other than DPD inhibition. The focus of the present study was to investigate the antitumor effects of CDHP and cisplatin (CDDP) combination treatment in vitro and in vivo against oral squamous cell carcinoma (OSCC) tumors...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28926616/co-ordinated-activation-of-classical-and-novel-pkc-isoforms-is-required-for-pma-induced-mtorc1-activation
#2
Mengling Liu, Christopher J Clarke, Mohamed F Salama, Yeon Ja Choi, Lina M Obeid, Yusuf A Hannun
Protein kinase C (PKC) has been shown to activate the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, a central hub in the regulation of cell metabolism, growth and proliferation. However, the mechanisms by which PKCs activate mTORC1 are still ambiguous. Our previous study revealed that activation of classical PKCs (cPKC) results in the perinuclear accumulation of cPKC and phospholipase D2 (PLD2) in recycling endosomes in a PLD2-dependent manner. Here, we report that mTORC1 activation by phorbol 12,13-myristate acetate (PMA) requires both classic, cPKC, and novel PKC (nPKC) isoforms, specifically PKCη, acting through distinct pathways...
2017: PloS One
https://www.readbyqxmd.com/read/28925388/structural-step-forward-for-nhej
#3
Go Watanabe, Michael R Lieber, Dewight Williams
In a recent paper published in Cell Research, a cryo-EM structure reveals the interface between DNA-PKcs and the Ku70/80:DNA complex, together forming the DNA-dependent protein kinase holoenzyme in non-homologous DNA end joining. Insight from this structure suggests how an allosteric rearrangement of DNA-PKcs driven by Ku70/80:DNA binding regulates kinase activity in this largest member of a family of structurally homologous phosphoinositide 3-kinase-related protein kinases that includes mTOR, ATR, and ATM.
September 19, 2017: Cell Research
https://www.readbyqxmd.com/read/28881569/aurora-a-kinase-regulates-non-homologous-end-joining-and-poly-adp-ribose-polymerase-function-in-ovarian-carcinoma-cells
#4
Thuy-Vy Do, Jeff Hirst, Stephen Hyter, Katherine F Roby, Andrew K Godwin
Ovarian cancer is usually diagnosed at late stages when cancer has spread beyond the ovary and patients ultimately succumb to the development of drug-resistant disease. There is an urgent and unmet need to develop therapeutic strategies that effectively treat ovarian cancer and this requires a better understanding of signaling pathways important for ovarian cancer progression. Aurora A kinase (AURKA) plays an important role in ovarian cancer progression by mediating mitosis and chromosomal instability. In the current study, we investigated the role of AURKA in regulating the DNA damage response and DNA repair in ovarian carcinoma cells...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28841900/activation-of-pkc-triggers-rescue-of-npc1-patient-specific-ipsc-derived-glial-cells-from-gliosis
#5
Franziska Peter, Sebastian Rost, Arndt Rolfs, Moritz J Frech
BACKGROUND: Niemann-Pick disease Type C1 (NPC1) is a rare progressive neurodegenerative disorder caused by mutations in the NPC1 gene. The pathological mechanisms, underlying NPC1 are not yet completely understood. Especially the contribution of glial cells and gliosis to the progression of NPC1, are controversially discussed. As an analysis of affected cells is unfeasible in NPC1-patients, we recently developed an in vitro model system, based on cells derived from NPC1-patient specific iPSCs...
August 25, 2017: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/28840859/cryo-em-structure-of-human-dna-pk-holoenzyme
#6
Xiaotong Yin, Mengjie Liu, Yuan Tian, Jiawei Wang, Yanhui Xu
DNA-dependent protein kinase (DNA-PK) is a serine/threonine protein kinase complex composed of a catalytic subunit (DNA-PKcs) and KU70/80 heterodimer bound to DNA. DNA-PK holoenzyme plays a critical role in non-homologous end joining (NHEJ), the major DNA repair pathway. Here, we determined cryo-electron microscopy structure of human DNA-PK holoenzyme at 6.6 Å resolution. In the complex structure, DNA-PKcs, KU70, KU80 and DNA duplex form a 650-kDa heterotetramer with 1:1:1:1 stoichiometry. The N-terminal α-solenoid (∼2 800 residues) of DNA-PKcs adopts a double-ring fold and connects the catalytic core domain of DNA-PKcs and KU70/80-DNA...
August 25, 2017: Cell Research
https://www.readbyqxmd.com/read/28838997/lack-of-constitutively-active-dna-repair-sensitizes-glioblastomas-to-akt-inhibition-and-induces-synthetic-lethality-with-radiation-treatment-in-a-p53-dependentmanner
#7
Kamalakannan Palanichamy, Disha Patel, John R Jacob, Kevin T Litzenberg, Nicolaus Gordon, Kirstin Acus, Shin-Ei Noda, Arnab Chakravarti
Treatment refractory glioblastoma (GBM) remains a major clinical problem globally and targeted therapies in GBM have not been promising to date. TCGA integrative analysis of GBM reported the striking finding of genetic alterations in the p53 and PI3K pathways in over 80% of GBMs. Given the role of these pathways in making cell-fate decisions and responding to genotoxic stress, we investigated the reliance of these two pathways in mediating radiation-resistance. We selected a panel of GBM cell lines and glioma stem cells (GSC) with wild-type TP53 (p53-wt) and mutant TP53, mutations known to interfere with p53 functionality (p53-mt)...
August 24, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28835051/-rna-interference-targeting-dna-pkcs-inhibits-glioma-cells-malignancies-and-enhances-temozolomide-sensitivity
#8
Z H Zhang, X Y Fan, Z T Zhao, Y M Song, C J Yu
Objective: To investigate the effect of DNA dependent protein kinase catalytic subunit (DNA-PKcs) on glioma proliferation, invasion and temozolomide sensitivity, and also to explore the potential mechanisms. Methods: Human glioma cell lines H4 and U87 were chosen to carry out RNA interference transfection, and then divided into negative control group (blank group) and siRNA group (test group). The knockdown efficacy of DNA-PKcs siRNA was tested by quantitative PCR and Western blot. The MTS assay and Transwell assay were used to investigate the effect of DNA-PKcs knockdown on glioma cell growth and invasion, respectively...
August 15, 2017: Zhonghua Yi Xue za Zhi [Chinese medical journal]
https://www.readbyqxmd.com/read/28827033/inhibition-of-parp1-activity-enhances-chemotherapeutic-efficiency-in-cisplatin-resistant-gastric-cancer-cells
#9
Qiang Wang, Jianping Xiong, Danping Qiu, Xue Zhao, Donglin Yan, Wenxia Xu, Zhangding Wang, Qi Chen, Sapna Panday, Aiping Li, Shouyu Wang, Jianwei Zhou
Cisplatin (DDP) is the first line chemotherapeutic drug for several cancers, including gastric cancer (GC). Unfortunately, the rapid development of drug resistance remains a significant challenge for the clinical application of cisplatin. There is an urgent need to develop new strategies to overcome DDP resistance for cancer treatment. In this study, four types of human GC cells have been divided into naturally sensitive or naturally resistant categories according to their responses to cisplatin. PARP1 activity (poly (ADP-ribose), PAR) was found to be greatly increased in cisplatin-resistant GC cells...
August 4, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28819445/dna-dependent-protein-kinase-catalytic-subunit-functions-in-metastasis-and-influences-survival-in-advanced-stage-laryngeal-squamous-cell-carcinoma
#10
Sha-Sha He, Yong Chen, Xiao-Ming Shen, Hong-Zhi Wang, Peng Sun, Jun Dong, Gui-Fang Guo, Ju-Gao Chen, Liang-Ping Xia, Pei-Li Hu, Hui-Juan Qiu, Shou-Sheng Liu, Yi-Xin Zhou, Wei Wang, Wei-Han Hu, Xiu-Yu Cai
Background: DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is known to function in several types of cancer. In this study, we investigated the expression and clinicopathologic significance of DNA-PKcs in laryngeal squamous cell carcinoma (LSCC). Methods: We conducted a retrospective study of 208 patients with advanced-stage LSCC treated at Sun Yat-sen University Cancer Center, Guangzhou, China. We assessed DNA-PKcs and p16INK4a (p16) status using immunohistochemistry. We examined the association between DNA-PKcs expression and clinicopathologic features and survival outcomes...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28802226/taraxerol-a-pentacyclic-triterpenoid-from-abroma-augusta-leaf-attenuates-diabetic-nephropathy-in-type-2-diabetic-rats
#11
Ritu Khanra, Niloy Bhattacharjee, Tarun K Dua, Ashis Nandy, Achintya Saha, Jatin Kalita, Prasenjit Manna, Saikat Dewanjee
Persistent hyperglycaemia coupled with inflammation plays an important role in the pathogenesis of diabetic nephropathy (DN). Present study examined the therapeutic potential of taraxerol isolated from the methanol extract of Abroma augusta leaf against DN using rodent model of type 2 diabetes (T2D). T2D was experimentally induced by high fat diet and a single low-single dose of streptozotocin (35mg/kg, i.p.). Accumulation of serum creatinine, urea, and uric acid, activation of lactate dehydrogenase and creatinin kinase, and release of urinary albumin represented the glomerular damage and the progression of nephropathy in T2D rats...
October 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28780472/different-profiles-of-the-mrna-levels-of-dna-repair-genes-in-mcf-7-and-sh-sy5y-cells-after-treatment-with-combination-of-cisplatin-50-hz-electromagnetic-field-and-bleomycin
#12
Fatemeh Sanie-Jahromi, Mostafa Saadat
Neurotoxicity is known to be a major dose-limiting adverse effect of cisplatin (CDDP), alone or in combination with other chemicals. DNA repair capacity serve as a neuroprotective factor against CDDP. The purpose of this study was to evaluate the effect of 50-Hz electromagnetic field (EMF) in combination with CDDP and bleomycin (Bleo) on expression of some of DNA repair genes (GADD45A, XRCC1, XRCC4, Ku70, Ku80, DNA-PKcs and LIG4) in MCF-7 (breast cancer) and SH-SY5Y (neuroblastoma) cell lines. MCF-7 and SH-SY5Y cells were pre-treated with CDDP in the presence or absence of EMF and then exposed to different concentration of Bleo...
October 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28771739/endostatin-sensitizes-p53-deficient-non-small-cell-lung-cancer-to-genotoxic-chemotherapy-by-targeting-dna-pkcs
#13
Lin Jia, Xin-An Lu, Guanghua Liu, Shan Wang, Min Xu, Yang Tian, Shaosen Zhang, Yan Fu, Yongzhang Luo
Endostatin was discovered as an endogenous angiogenesis inhibitor with broad-spectrum antitumor activities. Although clinical efficacy was observed when combining endostatin with standard chemotherapy for non-small cell lung cancer (NSCLC), as well as other cancer types, the specific mechanisms underlying the benefit of endostatin are not completely understood. Extensive investigations suggest that endostatin is a multifunctional protein possessing more than anti-angiogenic activity. Here, we identified that endostatin exerts a direct chemosensitizing effect on p53-deficient tumor cells...
August 3, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28767037/cryo-em-structure-of-the-saga-and-nua4-coactivator-subunit-tra1-at-3-7-angstrom-resolution
#14
Luis Miguel Díaz-Santín, Natasha Lukoyanova, Emir Aciyan, Alan Cm Cheung
Coactivator complexes SAGA and NuA4 stimulate transcription by post-translationally modifying chromatin. Both complexes contain the Tra1 subunit, a highly conserved 3744-residue protein from the Phosphoinositide 3-Kinase-related kinase (PIKK) family and a direct target for multiple sequence-specific activators. We present the Cryo-EM structure of Saccharomyces cerevsisae Tra1 to 3.7 Å resolution, revealing an extensive network of alpha-helical solenoids organized into a diamond ring conformation and is strikingly reminiscent of DNA-PKcs, suggesting a direct role for Tra1 in DNA repair...
August 2, 2017: ELife
https://www.readbyqxmd.com/read/28762752/oxidative-stress-in-mesenchymal-stem-cell-senescence-regulation-by-coding-and-non-coding-rnas
#15
Rosa Vono, Eva Jover Garcia, Gaia Spinetti, Paolo Madeddu
SIGNIFICANCE: Mesenchymal stem cells (MSCs), adult stem cells with the potential of differentiation into mesodermal lineages, play an important role in tissue homeostasis and regeneration. In different organs, a subpopulation of MSCs is located near to the vasculature and possibly represents the original source of lineage-committed mesenchymal progenitors. Recent Advances. The plasticity and immune characteristics of MSCs render them a preferential tool for regenerative cell therapy. CRITICAL ISSUES: The culture expansion needed before MSC transplantation is associated with cellular senescence...
August 1, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28761330/epigenetic-memory-of-oxidative-stress-does-nephrilin-exert-its-protective-effects-via-rac1
#16
Desmond D Mascarenhas, David N Herndon, Istvan Arany
AIM: Nephrilin peptide, a designed inhibitor of Rictor complex (mTORC2), exerts pleiotropic protective effects in metabolic, xenobiotic and traumatic stress models. Stress can generate enduring epigenetic changes in gene function. In this work we examine the possibility that nephrilin treatment protects against acute and enduring global changes in oxidative metabolism, with a focus on the Rictor-complex-mediated activation of Rac1, a subunit of NADPH oxidase (Nox) via PKCs, Prex1 and p66shc...
2017: Biologics: Targets & Therapy
https://www.readbyqxmd.com/read/28759779/synthetic-lethality-between-murine-dna-repair-factors-xlf-and-dna-pkcs-is-rescued-by-inactivation-of-ku70
#17
Mengtan Xing, Magnar Bjørås, Jeremy A Daniel, Frederick W Alt, Valentyn Oksenych
DNA double-strand breaks (DSBs) are recognized and repaired by the Classical Non-Homologous End-Joining (C-NHEJ) and Homologous Recombination pathways. C-NHEJ includes the core Ku70 and Ku80 (or Ku86) heterodimer that binds DSBs and thus promotes recruitment of accessory downstream NHEJ factors XLF, PAXX, DNA-PKcs, Artemis and other core subunits, XRCC4 and DNA Ligase 4 (Lig4). In the absence of core C-NHEJ factors, DNA repair can be performed by Alternative End-Joining, which likely depends on DNA Ligase 1 and DNA Ligase 3...
September 2017: DNA Repair
https://www.readbyqxmd.com/read/28758831/tet1-deficiency-attenuates-the-dna-damage-response-and-promotes-resistance-to-dna-damaging-agents
#18
Jonathan B Coulter, Hernando Lopez-Bertoni, Katherine J Kuhns, Richard S Lee, John Laterra, Joseph P Bressler
Recent studies have shown that loss of TET1 may play a significant role in the formation of tumors. Because genomic instability is a hallmark of cancer, we examined the potential involvement of ten-eleven translocation 1 (TET1) in the DNA damage response (DDR). Here we demonstrate that, in response to clinically relevant doses of ionizing radiation (IR), human glial cells made TET1-deficient with lentiviral vectors displayed greater numbers of colony forming units and lower levels of apoptotic markers compared to glial cells transduced with control vectors; yet, they harbored greater DNA strand breaks...
July 31, 2017: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/28758638/influenza-virus-recruits-host-protein-kinase-c-to-control-assembly-and-activity-of-its-replication-machinery
#19
Arindam Mondal, Anthony R Dawson, Gregory K Potts, Elyse C Freiberger, Steven F Baker, Lindsey A Moser, Kristen A Bernard, Joshua J Coon, Andrew Mehle
Influenza virus expresses transcripts early in infection and transitions towards genome replication at later time points. This process requires de novo assembly of the viral replication machinery, large ribonucleoprotein complexes (RNPs) composed of the viral polymerase, genomic RNA and oligomeric nucleoprotein (NP). Despite the central role of RNPs during infection, the factors dictating where and when they assemble are poorly understood. Here we demonstrate that human protein kinase C (PKC) family members regulate RNP assembly...
July 31, 2017: ELife
https://www.readbyqxmd.com/read/28750002/dna-pkcs-controls-calcineurin-mediated-il-2-production-in-t-lymphocytes
#20
Ara Kim Wiese, Marie Schluterman Burdine, Richard H Turnage, Alan J Tackett, Lyle J Burdine
Loss of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activity in mammals results in severe combined immuno-deficiency (SCID). This SCID phenotype has been postulated to be due solely to the function of DNA-PKcs in V(D)J recombination, a process critical for lymphocyte maturation. However; we show that DNA-PKcs is required for IL-2 production via regulation of the calcineurin signaling pathway. Reducing DNA-PKcs activity in activated T cells either by shRNA or an inhibitor significantly reduced IL-2 production by blocking calcineurin activity and the translocation of NFAT into the nucleus...
2017: PloS One
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