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So-Youn Kim, Devi M Nair, Megan Romero, Vanida A Serna, Anthony J Koleske, Teresa K Woodruff, Takeshi Kurita
Platinum-based chemotherapies can result in ovarian insufficiency by reducing the ovarian reserve, a reduction believed to result from apoptosis of immature oocytes via activation/phosphorylation of TAp63α by multiple kinases including CHEK2, CK1, and ABL1. Here we demonstrate that cisplatin (CDDP) induces oocyte apoptosis through a novel pathway and that temporary repression of this pathway fully preserves ovarian function in vivo. Although ABL kinase inhibitors effectively block CDDP-induced apoptosis of oocytes, oocytic ABL1, and ABL2 are dispensable for damage-induced apoptosis...
July 9, 2018: Cell Death and Differentiation
Shijia Wang, Yue Zhang, Min Chen, Yong Wang, Yifei Feng, Ziwei Xu, Dongsheng Zhang, Yueming Sun, Zan Fu
Objective: The ATR-CHEK1 and ATM-CHEK2 pathway have been confirmed to be related with the DNA damage response (DDR). Many studies have reported that genetic variants in ATR/CHEK1 and ATM/CHEK2 are associated with cancer risk. However, the association between genetic variants in ATR-CHEK1, ATM-CHEK2 pathway genes and colorectal cancer susceptibility is still unknown. In this study, we aim to explore whether these variants are correlated with the risk of colorectal cancer in a Chinese population...
June 1, 2018: Oncotarget
Song Xu, Renwang Liu, Yurong Da
BACKGROUND: This study compared tumor-related signaling pathways with known compounds to determine potential agents for lung adenocarcinoma (LUAD) treatment. METHODS: Kyoto Encyclopedia of Genes and Genomes signaling pathway analyses were performed based on LUAD differentially expressed genes from The Cancer Genome Atlas (TCGA) project and genotype-tissue expression controls. These results were compared to various known compounds using the Connectivity Mapping dataset...
June 5, 2018: Thoracic Cancer
Liang Zhao, Zhechao Zhang, Hongyan Lou, Jingjing Liang, Xiaojian Yan, Wenfeng Li, Yunsheng Xu, Rongying Ou
The molecular mechanisms of cervical cancer have been minimally explored with multi-omics data. In the present study, mRNA expression profiles were analyzed and combined with predicted miRNA interactions to contribute to the characterization of the underlying regulatory mechanisms of cervical cancer. A total of 92 significantly differentially expressed genes (DEGs) were identified in 33 tumor samples by comparison with 29 normal samples. mRNA-miRNA interaction network analysis revealed that 16 out of the 92 DEGs, including checkpoint kinase 1 ( CHEK1 ), SRY-box 17 ( SOX17 ), centrosomal protein 55, cyclin dependent kinase inhibitor 2A ( CDKN2A ), and inhibitor of DNA binding 4, were the targets of 4 miRNAs which were previously reported to be involved in the regulation of cervical cancer...
June 2018: Oncology Letters
Jun Yang, Ziming Hou, Changjiang Wang, Hao Wang, Hongbing Zhang
OBJECTIVE: High grade astrocytoma (HGA) as an aggressive brain tumor, is always correlated with poor prognosis. In this paper, we aimed to explore the genetic prognostic biomarkers for HGA. METHODS: The genome-wide expression profile of 26 brain tumor samples obtained from 26 patients with HGA was downloaded from Gene Expression Omnibus. The risk genes for prognosis of HGA were identified and verified by the data in TCGA database. Protein-protein interaction (PPI) network of risk factor genes was constructed and significant module was screened...
May 21, 2018: Neurological Research
Tomohiro Kondo, Masashi Kanai, Tadayuki Kou, Tomohiro Sakuma, Hiroaki Mochizuki, Mayumi Kamada, Masahiko Nakatsui, Norimitsu Uza, Yuzo Kodama, Toshihiko Masui, Kyoichi Takaori, Shigemi Matsumoto, Hidehiko Miyake, Yasushi Okuno, Manabu Muto
Objectives: We aimed to examine the association between homologous recombination repair (HRR)-related gene mutations and efficacy of oxaliplatin-based chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC). Results: Non-synonymous mutations in HRR-related genes were found in 13 patients and only one patient had a family history of pancreatic cancer. Eight patients with HRR-related gene mutations (group A) and nine without HRR-related gene mutations (group B) received oxaliplatin-based chemotherapy...
April 13, 2018: Oncotarget
Yan Wang, Xiaohui Sun, Lianying Fang, Keqiu Li, Ping Yang, Liqing Du, Kaihua Ji, Jinhan Wang, Qiang Liu, Chang Xu, Guang Li, John P Giesy, Markus Hecker
BACKGROUND: Managing and recycling electronic waste (e-waste), while useful and necessary, has resulted in significant contamination of several environments in China. The area around Tianjin, China has become one of the world's largest e-waste disposal centers, where electronics are processed by manually disassembly or burning, which can result in serious exposure of workers to a multitude of toxicants. OBJECTIVE: The present study assessed potential genomic damage in workers involved in recycling e-waste...
August 2018: Environment International
Hiroki Ide, Satoshi Inoue, Taichi Mizushima, Guiyang Jiang, Kuang-Hsiang Chuang, Mototsugu Oya, Hiroshi Miyamoto
Although radiotherapy often with chemotherapy has been shown to offer a survival benefit comparable with that of radical cystectomy in select patients with bladder cancer, the development of radiosensitization strategies may significantly enhance its application. Notably, emerging preclinical evidence has indicated the involvement of androgen receptor (AR) signaling in urothelial cancer progression. We here assessed whether AR signals could contribute to modulating radiosensitivity in bladder cancer cells. Ionizing radiation reduced the numbers of viable cells or colonies of AR-negative lines more significantly than those of AR-positive lines...
July 2018: Molecular Cancer Therapeutics
Xiaojie Yu, Yiqiang Zhang, Xiuye Ma, Alexander Pertsemlidis
Microtubule-targeting agents (MTAs) are widely used for the treatment of non-small cell lung cancer (NSCLC). The response rate is only ∼25%, mainly attributable to drug resistance. To identify determinants of resistance in NSCLC, we performed a high-throughput screen using a library of miRNA mimics. Here we report that miR-195 synergizes with MTAs to inhibit the growth of NSCLC cells in vitro, that increased expression of miR-195 sensitizes NSCLC cells to MTAs and that repression of miR-195 confers resistance to MTAs...
July 28, 2018: Cancer Letters
Sandra Martínez-Canales, Miguel López de Rodas, Miriam Nuncia-Cantarero, Raquel Páez, Eitan Amir, Balázs Győrffy, Atanasio Pandiella, Eva María Galán-Moya, Alberto Ocaña
Although early stage ovarian cancer is in most cases a curable disease, some patients relapse even with appropriate adjuvant treatment. Therefore, the identification of patient and tumor characteristics to better stratify risk and guide rational drug development is desirable. Using transcriptomic functional annotation followed by protein-protein interacting (PPI) network analyses, we identified functions that were upregulated and associated with detrimental outcome in patients with early stage ovarian cancer...
May 2018: Cancer Medicine
Zay Yar Oo, Alexander J Stevenson, Martina Proctor, Sheena M Daignault, Sebastian Walpole, Catherine Lanagan, James Chen, Dubravka Škalamera, Loredana Spoerri, Stephen A Ainger, Richard A Sturm, Nikolas K Haass, Brian Gabrielli
Purpose: Checkpoint kinase 1 inhibitors (CHEK1i) have single-agent activity in vitro and in vivo Here, we have investigated the molecular basis of this activity. Experimental Design: We have assessed a panel of melanoma cell lines for their sensitivity to the CHEK1i GNE-323 and GDC-0575 in vitro and in vivo The effects of these compounds on responses to DNA replication stress were analyzed in the hypersensitive cell lines. Results: A subset of melanoma cell lines is hypersensitive to CHEK1i-induced cell death in vitro , and the drug effectively inhibits tumor growth in vivo In the hypersensitive cell lines, GNE-323 triggers cell death without cells entering mitosis...
June 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Hironori Abe, Kris G Alavattam, Yasuko Kato, Diego H Castrillon, Qishen Pang, Paul R Andreassen, Satoshi H Namekawa
The continuity of life depends on mechanisms in the germline that ensure the integrity of the genome. The DNA damage response/checkpoint kinases ATM and ATR are essential signaling factors in the germline. However, it remains unknown how a downstream transducer, Checkpoint Kinase 1 (CHEK1 or CHK1), mediates signaling in the male germline. Here, we show that CHEK1 has distinct functions in both the mitotic and meiotic phases of the male germline in mice. In the mitotic phase, CHEK1 is required for the resumption of prospermatogonia proliferation after birth and the maintenance of spermatogonia...
April 1, 2018: Human Molecular Genetics
Yinghui Zhang, Lynn Wester, Jichao He, Tamar Geiger, Marja Moerkens, Ram Siddappa, Jean A Helmijr, Mieke M Timmermans, Maxime P Look, Caroline H M van Deurzen, John W M Martens, Chantal Pont, Marjo de Graauw, Erik H J Danen, Els M J J Berns, John H N Meerman, Maurice P H M Jansen, Bob van de Water
Antiestrogen resistance in estrogen receptor positive (ER+ ) breast cancer is associated with increased expression and activity of insulin-like growth factor 1 receptor (IGF1R). Here, a kinome siRNA screen has identified 10 regulators of IGF1R-mediated antiestrogen with clinical significance. These include the tamoxifen resistance suppressors BMPR1B, CDK10, CDK5, EIF2AK1, and MAP2K5, and the tamoxifen resistance inducers CHEK1, PAK2, RPS6KC1, TTK, and TXK. The p21-activated kinase 2, PAK2, is the strongest resistance inducer...
April 2018: Oncogene
Xiaobin Bai, Jia Wang, Longwei Huo, Yuchen Xie, Wanfu Xie, Gaofeng Xu, Maode Wang
Accumulating evidence indicates that Checkpoint kinase 1 (CHEK1) plays an essential role in tumor cells and that it could induce cell proliferation and could be related to prognosis in multiple types of cancer. However, the biological role and molecular mechanism of CHEK1 in GBM still remain unclear. In this study, we identified that CHEK1 expression was enriched in glioblastoma (GBM) tumors and was functionally required for tumor proliferation and that its expression was associated to poor prognosis in GBM patients...
February 2018: Translational Oncology
Akihiro Ohmoto, Shinichi Yachida
Inhibitors of poly(ADP-ribose) polymerases (PARPs), which play a key role in DNA damage/repair pathways, have been developed as antitumor agents based on the concept of synthetic lethality. Synthetic lethality is the idea that cell death would be efficiently induced by simultaneous loss of function of plural key molecules, for example, by exposing tumor cells with inactivating gene mutation of BRCA-mediated DNA repair to chemically induced inhibition of PARPs. Indeed, three PARP inhibitors, olaparib, rucaparib and niraparib have already been approved in the US or Europe, mainly for the treatment of BRCA -mutant ovarian cancer...
2017: OncoTargets and Therapy
Fabian Doerr, Julie George, Anna Schmitt, Filippo Beleggia, Tim Rehkämper, Sarah Hermann, Vonn Walter, Jean-Philip Weber, Roman K Thomas, Maike Wittersheim, Reinhard Büttner, Thorsten Persigehl, H Christian Reinhardt
Small cell lung cancer (SCLC) is a difficult to treat subtype of lung cancer. One of the hallmarks of SCLC is its almost uniform chemotherapy sensitivity. However, chemotherapy response is typically transient and patients frequently succumb to SCLC within a year following diagnosis. We performed a transcriptome analysis of the major human lung cancer entities. We show a significant overexpression of genes involved in the DNA damage response, specifically in SCLC. Particularly CHEK1, which encodes for the cell cycle checkpoint kinase CHK1, is significantly overexpressed in SCLC, compared to lung adenocarcinoma...
November 14, 2017: Scientific Reports
Naoki Kawahara, Kenji Ogawa, Mika Nagayasu, Mai Kimura, Yoshikazu Sasaki, Hiroshi Kobayashi
Inhibitors of poly(ADP-ribose) polymerase (PARP) are new types of personalized treatment of relapsed platinum-sensitive ovarian cancer harboring BRCA1/2 mutations. Ovarian clear cell cancer (CCC), a subset of ovarian cancer, often appears as low-stage disease with a higher incidence among Japanese. Advanced CCC is highly aggressive with poor patient outcome. The aim of the present study was to determine the potential synthetic lethality gene pairs for PARP inhibitions in patients with CCC through virtual and biological screenings as well as clinical studies...
November 2017: Biomedical Reports
Henry Okuchukwu Ebili, Victoria O Iyawe, Kikelomo Rachel Adeleke, Babatunde Abayomi Salami, Adekunbiola Aina Banjo, Chris Nolan, Emad Rakha, Ian Ellis, Andrew Green, Ayodeji Olayinka Johnson Agboola
BACKGROUND: Checkpoint kinase 1 (CHEK1), a DNA damage sensor and cell death pathway stimulator, is regarded as an oncogene in tumours, where its activities are considered essential for tumourigenesis and the survival of cancer cells treated with chemotherapy and radiotherapy. In breast cancer, CHEK1 expression has been associated with an aggressive tumour phenotype, the triple-negative breast cancer subtype, an aberrant response to tamoxifen, and poor prognosis. However, the relevance of CHEK1 expression has, hitherto, not been investigated in an indigenous African population...
February 2018: Molecular Diagnosis & Therapy
Masatoshi Takagi, Misa Yoshida, Yoshino Nemoto, Hiroyuki Tamaichi, Rika Tsuchida, Masafumi Seki, Kumiko Uryu, Rina Nishii, Satoshi Miyamoto, Masahiro Saito, Ryoji Hanada, Hideo Kaneko, Satoru Miyano, Keisuke Kataoka, Kenichi Yoshida, Miki Ohira, Yasuhide Hayashi, Akira Nakagawara, Seishi Ogawa, Shuki Mizutani, Junko Takita
Background: Neuroblastoma (NB) is the most common solid tumor found in children, and deletions within the 11q region are observed in 11% to 48% of these tumors. Notably, such tumors are associated with poor prognosis; however, little is known regarding the molecular targets located in 11q. Methods: Genomic alterations of ATM , DNA damage response (DDR)-associated genes located in 11q ( MRE11A, H2AFX , and CHEK1 ), and BRCA1, BARD1, CHEK2, MDM2 , and TP53 were investigated in 45 NB-derived cell lines and 237 fresh tumor samples...
November 1, 2017: Journal of the National Cancer Institute
Inger Brandsma, Emmy D G Fleuren, Chris T Williamson, Christopher J Lord
Defects in the DNA damage response (DDR) drive the development of cancer by fostering DNA mutation but also provide cancer-specific vulnerabilities that can be exploited therapeutically. The recent approval of three different PARP inhibitors for the treatment of ovarian cancer provides the impetus for further developing targeted inhibitors of many of the kinases involved in the DDR, including inhibitors of ATR, ATM, CHEK1, CHEK2, DNAPK and WEE1. Areas covered: We summarise the current stage of development of these novel DDR kinase inhibitors, and describe which predictive biomarkers might be exploited to direct their clinical use...
December 2017: Expert Opinion on Investigational Drugs
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