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Checkpoint kinase 1

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https://www.readbyqxmd.com/read/28442891/spotlight-on-nivolumab-in-the-treatment-of-renal-cell-carcinoma-design-development-and-place-in-therapy
#1
REVIEW
Vyshak Alva Venur, Monika Joshi, Kenneth G Nepple, Yousef Zakharia
Several tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptors and molecules inhibiting the mammalian target of rapamycin are being used for management of metastatic renal cell carcinoma (mRCC); however, there is still a potential for improvement. Immune checkpoint inhibitors like nivolumab and other PD-1/PD-L1 inhibitors provide an alternative approach for patients with mRCC. In this article, the authors review the safety profile and outcomes of phase 1, 2, and 3 clinical trials of nivolumab in mRCC...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28441348/deoxynucleoside-salvage-in-fission-yeast-allows-rescue-of-ribonucleotide-reductase-deficiency-but-not-spd1-mediated-inhibition-of-replication
#2
Oliver Fleck, Ulrik Fahnøe, Katrine Vyff Løvschal, Marie-Fabrice Uwamahoro Gasasira, Irina N Marinova, Birthe B Kragelund, Antony M Carr, Edgar Hartsuiker, Christian Holmberg, Olaf Nielsen
In fission yeast, the small, intrinsically disordered protein S-phase delaying protein 1 (Spd1) blocks DNA replication and causes checkpoint activation at least in part, by inhibiting the enzyme ribonucleotide reductase, which is responsible for the synthesis of DNA. The CRL4(Cdt2) E3 ubiquitin ligase mediates degradation of Spd1 and the related protein Spd2 at S phase of the cell cycle. We have generated a conditional allele of CRL4(Cdt2), by expressing the highly unstable substrate-recruiting protein Cdt2 from a repressible promoter...
April 25, 2017: Genes
https://www.readbyqxmd.com/read/28436952/playing-polo-during-mitosis-plk1-takes-the-lead
#3
REVIEW
G Combes, I Alharbi, L G Braga, S Elowe
Polo-like kinase 1 (PLK1), the prototypical member of the polo-like family of serine/threonine kinases, is a pivotal regulator of mitosis and cytokinesis in eukaryotes. Many layers of regulation have evolved to target PLK1 to different subcellular structures and to its various mitotic substrates in line with its numerous functions during mitosis. Collective work is starting to illuminate an important set of substrates for PLK1: the mitotic kinases that together ensure the fidelity of the cell division process...
April 24, 2017: Oncogene
https://www.readbyqxmd.com/read/28430840/checkpoint-dependent-phosphorylation-of-med1-trap220-in-response-to-dna-damage
#4
Hyun-Ju Kim, Jeanho Yun
Mediator complex subunit 1 (Med1)/Thyroid hormone receptor-associated protein 220 (TRAP220), an essential component of thyroid hormone receptor-associated proteins (TRAP)/mediator, plays important roles in hormone responses and tumorigenesis. However, the role of Med1 in the DNA damage response has not been studied. In this study, we found that DNA damage, resulted from γ-irradiation, ultraviolet (UV)-irradiation, or hydroxyurea, induced phosphorylation of Med1 in vivo. Phosphorylation of Med1 was abrogated by either caffeine or wortmannin treatment, suggesting that Med1 is phosphorylated through the DNA damage checkpoint pathway...
April 19, 2017: Acta Biochimica et Biophysica Sinica
https://www.readbyqxmd.com/read/28416123/immune-checkpoint-inhibitors-for-patients-with-advanced-non-small-cell-lung-cancer-a%C3%A2-systematic-review
#5
REVIEW
Peter M Ellis, Emily T Vella, Yee C Ung
Second-line treatment options are limited for patients with advanced non-small-cell lung cancer (NSCLC). Standard therapy includes the cytotoxic agents docetaxel and pemetrexed, and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib and gefitinib. Immune checkpoint inhibitors are a new class of treatment that have shown durable overall radiologic response rates and have been well tolerated. The objective of this systematic review was to investigate the efficacy of immune checkpoint inhibitors compared with other chemotherapies in patients with advanced NSCLC...
February 16, 2017: Clinical Lung Cancer
https://www.readbyqxmd.com/read/28415805/regulatory-functional-territory-of-plk-1-and-their-substrates-beyond-mitosis
#6
REVIEW
Shiv Kumar, Garima Sharma, Chiranjib Chakraborty, Ashish Ranjan Sharma, Jaebong Kim
Polo-like kinase 1 (PLK-1) is a well-known (Ser/Thr) mitotic protein kinase and is considered as a proto-oncogene. As hyper-activation of PLK-1 is broadly associated with poor prognosis and cancer progression, it is one of the most extensively studied mitotic kinases. During mitosis, PLK-1 regulates various cell cycle events, such as spindle pole maturation, chromosome segregation and cytokinesis. However, studies have demonstrated that the role of PLK-1 is not only restricted to mitosis, but PLK-1 can also regulate other vital events beyond mitosis, including transcription, translation, ciliogenesis, checkpoint adaptation and recovery, apoptosis, chromosomes dynamics etc...
March 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415748/the-spi1-pu-1-transcription-factor-accelerates-replication-fork-progression-by-increasing-pp1-phosphatase-in-leukemia
#7
Pauline Rimmelé, Michela Esposito, Laure Delestré, Jean-Hugues Guervilly, Maya Ridinger-Saison, Emmanuelle Despras, Françoise Moreau-Gachelin, Filippo Rosselli, Christel Guillouf
Oncogenes trigger replicative stress that can lead to genetic instability, which participates in cancer progression. Thus, determining how cells cope with replicative stress can help our understanding of oncogenesis and lead to the identification of new antitumor treatment targets. We previously showed that constitutive overexpression of the oncogenic transcription factor Spi1/PU.1 leads to pre-leukemic cells that have a shortened S phase duration with an increased replication fork speed and increased mutability in the absence of DNA breaks...
March 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28405494/overcoming-resistance-to-her2-targeted-therapy-with-a-novel-her2-cd3-bispecific-antibody
#8
Andres Lopez-Albaitero, Hong Xu, Hongfen Guo, Linlin Wang, Zhihao Wu, Hoa Tran, Sarat Chandarlapaty, Maurizio Scaltriti, Yelena Janjigian, Elisa de Stanchina, Nai-Kong V Cheung
T-cell-based therapies have emerged as one of the most clinically effective ways to target solid and non-solid tumors. HER2 is responsible for the oncogenesis and treatment resistance of several human solid tumors. As a member of the HER family of tyrosine kinase receptors, its over-activity confers unfavorable clinical outcome. Targeted therapies directed at this receptor have achieved responses, although development of resistance is common. We explored a novel HER2/CD3 bispecific antibody (HER2-BsAb) platform that while preserving the anti-proliferative effects of trastuzumab, it recruits and activates non-specific circulating T-cells, promoting T cell tumor infiltration and ablating HER2(+) tumors, even when these are resistant to standard HER2-targeted therapies...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28401005/chk1-inhibition-potentiates-the-therapeutic-efficacy-of-parp-inhibitor-bmn673-in-gastric-cancer
#9
Yuping Yin, Qian Shen, Peng Zhang, Ruikang Tao, Weilong Chang, Ruidong Li, Gengchen Xie, Weizhen Liu, Lihong Zhang, Prabodh Kapoor, Shumei Song, Jaffer Ajani, Gordon B Mills, Jianying Chen, Kaixiong Tao, Guang Peng
Globally, gastric cancer is the second leading cause of cancer deaths because of the lack of effective treatments for patients with advanced tumors when curative surgery is not possible. Thus, there is an urgent need to identify molecular targets in gastric cancer that can be used for developing novel therapies and prolonging patient survival. Checkpoint kinase 1 (Chk1) is a crucial regulator of cell cycle transition in DNA damage response (DDR). In our study, we report that Chk1 plays an important role in promoting gastric cancer cell survival and growth, which serves as an effective therapeutic target in gastric cancer...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28389531/chk1-targeted-therapy-to-deplete-dna-replication-stressed-p53-deficient-hyperdiploid-colorectal-cancer-stem-cells
#10
Gwenola Manic, Michele Signore, Antonella Sistigu, Giorgio Russo, Francesca Corradi, Silvia Siteni, Martina Musella, Sara Vitale, Maria Laura De Angelis, Matteo Pallocca, Carla Azzurra Amoreo, Francesca Sperati, Simone Di Franco, Sabina Barresi, Eleonora Policicchio, Gabriele De Luca, Francesca De Nicola, Marcella Mottolese, Ann Zeuner, Maurizio Fanciulli, Giorgio Stassi, Marcello Maugeri-Saccà, Marta Baiocchi, Marco Tartaglia, Ilio Vitale, Ruggero De Maria
OBJECTIVE: Cancer stem cells (CSCs) are responsible for tumour formation and spreading, and their targeting is required for tumour eradication. There are limited therapeutic options for advanced colorectal cancer (CRC), particularly for tumours carrying RAS-activating mutations. The aim of this study was to identify novel CSC-targeting strategies. DESIGN: To discover potential therapeutics to be clinically investigated as single agent, we performed a screening with a panel of FDA-approved or investigational drugs on primary CRC cells enriched for CSCs (CRC-SCs) isolated from 27 patients...
April 7, 2017: Gut
https://www.readbyqxmd.com/read/28380042/genetic-and-pharmacological-inhibition-of-ttk-impairs-pancreatic-cancer-cell-line-growth-by-inducing-lethal-chromosomal-instability
#11
Jeran K Stratford, Feng Yan, Rebecca A Hill, Michael B Major, Lee M Graves, Channing J Der, Jen Jen Yeh
Pancreatic ductal adenocarcinoma, which accounts for the majority of pancreatic cancers, is a lethal disease with few therapeutic options. Genomic profiling of pancreatic ductal adenocarcinoma has identified a complex and heterogeneous landscape. Understanding the molecular characteristics of pancreatic ductal adenocarcinoma will facilitate the identification of potential therapeutic strategies. We analyzed the gene expression profiles of primary tumors from patients compared to normal pancreas and identified high co-overexpression of core components of the spindle assembly checkpoint, including the protein kinase TTK (also known as MPS-1)...
2017: PloS One
https://www.readbyqxmd.com/read/28373435/clinical-significance-of-dna-damage-response-factors-and-chromosomal-instability-in-primary-lung-adenocarcinoma
#12
COMPARATIVE STUDY
Tatsuro Okamoto, Mikihiro Kohno, Kensaku Ito, Kazuki Takada, Masakazu Katsura, Yosuke Morodomi, Gouji Toyokawa, Fumihiro Shoji, Yoshihiko Maehara
AIM: The purpose of this study was to investigate the biological role of DNA damage-response genes and chromosomal instability in primary lung adenocarcinoma. MATERIALS AND METHODS: We investigated 60 surgically-resected lung adenocarcinomas. Levels of checkpoint kinase 2 gene (CHEK2) and breast cancer type 1 susceptibility protein gene (BRCA1) mRNA expression were evaluated by polymerase chain reaction (PCR). Epidermal growth factor receptor (EGFR) mutations (exon 19 deletion and exon 21 mutation) were detected by the PCR clamp method...
April 2017: Anticancer Research
https://www.readbyqxmd.com/read/28364522/spindlin-1-is-essential-for-metaphase-ii-stage-maintenance-and-chromosomal-stability-in-porcine-oocytes
#13
Jeong-Woo Choi, Ming-Hui Zhao, Shuang Liang, Jing Guo, Zi-Li Lin, Ying-Hua Li, Yu-Jin Jo, Nam-Hyung Kim, Xiang-Shun Cui
Study question: What is the function of Spindlin 1 (Spin1) in metaphase II stage oocytes in pigs? Summary answer: Depletion of Spin1 induces spontaneous oocyte activation and overexpression of Spin1 causes multinuclear formation through induction of DNA damage in porcine oocytes. What is known already: Little is known about the function of Spin1 in oocytes and embryos. In mouse oocytes, Spin1 is specifically expressed during gametogenesis and is essential for meiotic resumption...
March 1, 2017: Molecular Human Reproduction
https://www.readbyqxmd.com/read/28356985/molecular-mechanisms-of-cholangiocarcinoma-cell-inhibition-by-medicinal-plants
#14
Surang Leelawat, Kawin Leelawat
Cholangiocarcinoma (CCA) is one of the most common causes of cancer-associated mortality in Thailand. Certain phytochemicals have been demonstrated to modulate apoptotic signaling pathways, which may be targeted for the prevention and treatment of cancer. Therefore, the aim of the present study was to investigate the effect of specific medicinal plants on the inhibition of CCA cell proliferation, and to identify the molecular mechanisms underlying this. A WST-1 cell proliferation assay was performed using an RMCCA1 cell line, and apoptotic signaling pathways were also investigated using a PathScan Stress and Apoptosis Signaling Antibody Array Kit...
February 2017: Oncology Letters
https://www.readbyqxmd.com/read/28351953/sphingosine-1-phosphate-signaling-through-its-receptor-s1p5-promotes-chromosome-segregation-and-mitotic-progression
#15
Guillaume Andrieu, Adeline Ledoux, Sophie Branka, Magalie Bocquet, Julia Gilhodes, Thierry Walzer, Kousuke Kasahara, Masaki Inagaki, Roger A Sabbadini, Olivier Cuvillier, Anastassia Hatzoglou
Sphingosine kinase 1 (SphK1) promotes cell proliferation and survival, and its abundance is often increased in tumors. SphK1 produces the signaling lipid sphingosine 1-phosphate (S1P), which activates signaling cascades downstream five G protein-coupled receptors (S1P1-5) to modulate vascular and immune system function and promote proliferation. We identified a new function of the SphK1-S1P pathway specifically in the control of mitosis. SphK1 depletion in HeLa cells caused prometaphase arrest, whereas its overexpression or activation accelerated mitosis...
March 28, 2017: Science Signaling
https://www.readbyqxmd.com/read/28349497/alternative-chk1-independent-s-m-checkpoint-in-somatic-cells-that-prevents-premature-mitotic-entry
#16
Doaa Hussein Zineldeen, Noha Mohamed Shafik, Sheng Fan Li
Genomic instability is the hallmark of cancer. Checkpoint kinase-1 (Chk1) is required for cell cycle delay after DNA damage or blocked DNA replication. Chk1-depleted tumor cells undergo premature mitosis and apoptosis. Here we analyzed the depletion of Chk1 in normal somatic cells in the absence of DNA damage in order to investigate alternative cell cycle checkpoint mechanism(s). By means of adenoviruses, flow cytometry, immunofluorescence and Western blotting, Chk1-depleted mouse embryonic fibroblasts (MEFs) were investigated...
April 2017: Medical Oncology
https://www.readbyqxmd.com/read/28348080/a-positive-feedback-loop-between-pim-1-kinase-and-hbp1-transcription-factor-contributes-to-hydrogen-peroxide-induced-premature-senescence-and-apoptosis
#17
Shuya Wang, Zhengyi Cao, Junhui Xue, Hui Li, Wei Jiang, Yuning Cheng, Gang Li, Xiaowei Zhang
Oxidative stress can induce cell dysfunction and lead to a broad range of degenerative alterations including carcinogenesis, aging, and other oxidative stress-related conditions. To avoid undergoing carcinogenesis in response to oxidative stress, cells trigger a succession of checkpoint responses, including premature senescence and apoptosis. Increasing evidence indicates that H2O2, an important cause of oxidative stress, functions as an important physiological regulator of intracellular signaling pathways that participate in regulation of cell premature senescence and apoptosis...
March 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28330872/nadph-oxidase-1-supports-proliferation-of-colon-cancer-cells-by-modulating-reactive-oxygen-species-dependent-signal-transduction
#18
Agnes Juhasz, Susan Markel, Shikha Gaur, Han Liu, Jiamo Lu, Guojian Jiang, Xiwei Wu, Smitha Antony, Yongzhong Wu, Giovanni Melillo, Jennifer L Meitzler, Diana C Haines, Donna Butcher, Krishnendu Roy, James H Doroshow
Reactive oxygen species (ROS) play a critical role in cell signaling and proliferation. NADPH oxidase 1 (NOX1), a membrane-bound flavin dehydrogenase that generates superoxide, is highly expressed in colon cancer. To investigate the role that NOX1 plays in colon cancer growth, we used shRNA to decrease NOX1 expression stably in HT-29 human colon cancer cells. The 80-90% decrease in NOX1 expression achieved by RNAi produced a significant decline in ROS production and a G1/S block that translated into a 2-3-fold increase in tumor cell doubling time without increased apoptosis...
March 22, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28315636/pembrolizumab-for-metastatic-melanoma-in-a-renal-allograft-recipient-with-subsequent-graft-rejection-and-treatment-response-failure-a-case-report
#19
Vineet Kwatra, Narayan V Karanth, Kelum Priyadarshana, Michail Charakidis
BACKGROUND: Transplant patients were excluded from the pivotal phase III trials of checkpoint inhibitors in metastatic melanoma. The efficacy and toxicity profiles of checkpoint inhibitors in this cohort of patients are not well described. To the best of our knowledge, this is the first case report of a renal transplant patient with stage IV melanoma treated with a programmed cell death protein 1 checkpoint inhibitor that led to both treatment failure and renal graft rejection. CASE PRESENTATION: We present a case of a 58-year-old white man with a long-standing cadaveric renal transplant who was diagnosed with a B-Raf Proto-Oncogene, Serine/Threonine Kinase wild-type metastatic melanoma...
March 19, 2017: Journal of Medical Case Reports
https://www.readbyqxmd.com/read/28303169/diallyl-trisulfide-suppresses-oxidative-stress-induced-activation-of-hepatic-stellate-cells-through-production-of-hydrogen-sulfide
#20
Feng Zhang, Huanhuan Jin, Li Wu, Jiangjuan Shao, Xiaojing Zhu, Anping Chen, Shizhong Zheng
Accumulating data reveal that garlic has beneficial effects against chronic liver disease. We previously reported that diallyl trisulfide (DATS), the primary organosulfur compound in garlic, reduced fibrosis and attenuated oxidative stress in rat fibrotic liver. The present study was aimed at elucidating the underlying mechanisms. The primary rat hepatic stellate cells (HSCs) were cultured and stimulated with hydrogen peroxide (H2O2) for inducing HSC activation under oxidative stress. We examined the effects of DATS on the profibrogenic properties and oxidative stress in H2O2-treated HSCs...
2017: Oxidative Medicine and Cellular Longevity
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