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Mitotic catastrophe

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https://www.readbyqxmd.com/read/29262321/bet-bromodomain-inhibition-synergizes-with-parp-inhibitor-in-epithelial-ovarian-cancer
#1
Sergey Karakashev, Hengrui Zhu, Yuhki Yokoyama, Bo Zhao, Nail Fatkhutdinov, Andrew V Kossenkov, Andrew J Wilson, Fiona Simpkins, David Speicher, Dineo Khabele, Benjamin G Bitler, Rugang Zhang
PARP inhibition is known to be an effective clinical strategy in BRCA mutant cancers, but PARP inhibition has not been applied to BRCA-proficient tumors. Here, we show the synergy of BET bromodomain inhibition with PARP inhibition in BRCA-proficient ovarian cancers due to mitotic catastrophe. Treatment of BRCA-proficient ovarian cancer cells with the BET inhibitor JQ1 downregulated the G2-M cell-cycle checkpoint regulator WEE1 and the DNA-damage response factor TOPBP1. Combining PARP inhibitor Olaparib with the BET inhibitor, we observed a synergistic increase in DNA damage and checkpoint defects, which allowed cells to enter mitosis despite the accumulation of DNA damage, ultimately causing mitotic catastrophe...
December 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/29259156/dual-blockade-of-the-lipid-kinase-pip4ks-and-mitotic-pathways-leads-to-cancer-selective-lethality
#2
Mayumi Kitagawa, Pei-Ju Liao, Kyung Hee Lee, Jasmine Wong, See Cheng Shang, Noriaki Minami, Oltea Sampetrean, Hideyuki Saya, Dai Lingyun, Nayana Prabhu, Go Ka Diam, Radoslaw Sobota, Andreas Larsson, Pär Nordlund, Frank McCormick, Sujoy Ghosh, David M Epstein, Brian W Dymock, Sang Hyun Lee
Achieving robust cancer-specific lethality is the ultimate clinical goal. Here, we identify a compound with dual-inhibitory properties, named a131, that selectively kills cancer cells, while protecting normal cells. Through an unbiased CETSA screen, we identify the PIP4K lipid kinases as the target of a131. Ablation of the PIP4Ks generates a phenocopy of the pharmacological effects of PIP4K inhibition by a131. Notably, PIP4Ks inhibition by a131 causes reversible growth arrest in normal cells by transcriptionally upregulating PIK3IP1, a suppressor of the PI3K/Akt/mTOR pathway...
December 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/29237818/mps1-promotes-chromosome-meiotic-chromosome-bi-orientation-through-dam1
#3
Régis E Meyer, Jamin Brown, Lindsay Beck, Dean S Dawson
In budding yeast meiosis, homologous chromosomes become linked by chiasmata and then move back and forth on the spindle until they are bi-oriented - with the kinetochores of the partners attached to microtubules from opposite spindle poles. Certain mutations in the conserved kinase, Mps1, result in catastrophic meiotic segregation errors but mild mitotic defects. We tested whether Dam1, a known substrate of Mps1 was necessary for its critical meiotic role. We found that kinetochore-microtubule attachments are established even when Dam1 is not phosphorylated by Mps1, but that Mps1 phosphorylation of Dam1 sustains those connections...
December 13, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29217775/chemotherapy-induced-differential-cell-cycle-arrest-in-b-cell-lymphomas-affects-their-sensitivity-to-wee1-inhibition
#4
Xiaoguang Wang, Zhangguo Chen, Ameet K Mishra, Alexa Silva, Wenhua Ren, Zenggang Pan, Jing H Wang
Chemotherapeutic agents, e.g., cytarabine or doxorubicin cause DNA damages. However, it remains unknown whether such agents differentially regulate cell cycle arrest in distinct types of B cell lymphomas, and whether this phenotype can be exploited for developing new therapies. Here, we treated various types of B cells including primary and B lymphoma cells, with cytarabine or doxorubicin, and determined DNA damage responses, cell cycle regulation and sensitivity to Wee1 inhibitor. We found that cyclin A2/B1 upregulation appear to be an intrinsic programmed response to DNA damage; however, different types of B cells arrest in distinct phases of cell cycle...
December 7, 2017: Haematologica
https://www.readbyqxmd.com/read/29199006/lb-100-a-novel-protein-phosphatase-2a-pp2a-inhibitor-sensitizes-malignant-meningioma-cells-to-the-therapeutic-effects-of-radiation
#5
Winson S C Ho, Saman Sizdahkhani, Shuyu Hao, Hua Song, Ashlee Seldomridge, Anita Tandle, Dragan Maric, Tamalee Kramp, Rongze Lu, John D Heiss, Kevin Camphausen, Mark R Gilbert, Zhengping Zhuang, Deric M Park
Atypical and anaplastic meningiomas (AAM) represent 20% of all meningiomas. They are associated with poor outcomes due to their tendency to recur. While surgery and radiation (RT) are first line therapy, no effective systemic medical treatment has been identified. Protein phosphatase 2A (PP2A) is a ubiquitously expressed serine/threonine phosphatase involved in cell cycle regulation and DNA repair. Here, we examined radiosensitizing effects of LB-100, a novel inhibitor of PP2A against AAM as a novel treatment strategy...
November 30, 2017: Cancer Letters
https://www.readbyqxmd.com/read/29196537/esco1-2-s-roles-in-chromosome-structure-and-interphase-chromatin-organization
#6
Ryotaro Kawasumi, Takuya Abe, Hiroshi Arakawa, Massimiliano Garre, Kouji Hirota, Dana Branzei
ESCO1/2 acetyltransferases mediating SMC3 acetylation and sister chromatid cohesion (SCC) are differentially required for genome integrity and development. Here we established chicken DT40 cell lines with mutations in ESCO1/2, SMC3 acetylation, and the cohesin remover WAPL. Both ESCO1 and ESCO2 promoted SCC, while ESCO2 was additionally and specifically required for proliferation and centromere integrity. ESCO1 overexpression fully suppressed the slow proliferation and centromeric separation phenotypes of esco2 cells but only partly suppressed its chromosome arm SCC defects...
December 1, 2017: Genes & Development
https://www.readbyqxmd.com/read/29190084/acovenoside-a-induces-mitotic-catastrophe-followed-by-apoptosis-in-non-small-cell-lung-cancer-cells
#7
Menna El Gaafary, Shahira M Ezzat, Abeer M El Sayed, Omar M Sabry, Susanne Hafner, Sophia Lang, Michael Schmiech, Tatiana Syrovets, Thomas Simmet
We investigated the cytotoxic potential of the cardenolide glycoside acovenoside A against non-small-cell lung cancer cells. Lung cancer is the leading cause of cancer-related mortality and the second most common cancer diagnosed. Epidemiological studies revealed a direct correlation between the regular administration of cardiac glycosides and a lower incidence of various cancers. Acovenoside A, isolated from the pericarps of Acokanthera oppositifolia, potently inhibited proliferation and induced cytotoxicity in A549 non-small-cell lung cancer cells with an IC50 of 68 ± 3 nM after 48 h of exposure...
November 30, 2017: Journal of Natural Products
https://www.readbyqxmd.com/read/29187577/prc1e-and-kif4a-control-microtubule-organization-within-and-between-large-xenopus-egg-asters
#8
P A Nguyen, C M Field, T J Mitchison
The cleavage furrow in Xenopus zygotes is positioned by two large microtubule asters that grow out from the poles of the 1st mitotic spindle. Where these asters meet at the midplane they assemble a disc-shaped interaction zone consisting of anti-parallel microtubule bundles coated with chromosome passenger complex (CPC) and centralspindlin which instructs the cleavage furrow. Here, we investigate the mechanism that keeps the two asters separate, and forms a distinct boundary between them, focusing on the conserved cytokinesis midzone proteins Prc1 and Kif4A...
November 29, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29169283/time-lapse-microscopic-observation-of-non-dividing-cells-in-cultured-human-osteosarcoma-mg-63-cell-line
#9
John Dosch, Elise Hadley, Cal Wiese, Marissa Soderberg, Tori Houwman, Kai Ding, Alexandra Kharazova, John L Collins, Bart van Knippenberg, Carl Gregory, Alexander Kofman
Cancer stem cells resemble normal tissue-specific stem cells in many aspects, such as self-renewal and plasticity. Like their non-malignant counterparts, cancer stem cells are suggested to exhibit a relative quiescence. The established cancer cell lines reportedly harbor slow-proliferating cells that are positive for some cancer stem cells markers. However, the fate of these cells and their progeny remains unknown. We used time-lapse microscopy and the contrast-based segmentation algorithm to identify and monitor actively dividing and non-dividing cells in human osteosarcoma MG-63 cell line...
November 23, 2017: Cell Cycle
https://www.readbyqxmd.com/read/29157749/mithramycin-a-enhances-tumor-sensitivity-to-mitotic-catastrophe-resulting-from-dna-damage
#10
Bradley T Scroggins, Jeffrey Burkeen, Ayla O White, Eun Joo Chung, Darmood Wei, Su I Chung, Luca F Valle, Shilpa S Patil, Grace McKay-Corkum, Kathryn E Hudak, W Marston Linehan, Deborah E Citrin
PURPOSE: Specificity protein 1 (SP1) is involved in the transcription of several genes implicated in tumor maintenance. We investigated the effects of mithramycin A (MTA), an inhibitor of SP1 DNA binding, on radiation response. METHODS AND MATERIALS: Clonogenic survival after irradiation was assessed in 2 tumor cell lines (A549, UM-UC-3) and 1 human fibroblast line (BJ) after SP1 knockdown or MTA treatment. DNA damage repair was evaluated using γH2AX foci formation, and mitotic catastrophe was assessed using nuclear morphology...
October 12, 2017: International Journal of Radiation Oncology, Biology, Physics
https://www.readbyqxmd.com/read/29155723/one-step-protocol-for-evaluation-of-the-mode-of-radiation-induced-clonogenic-cell-death-by-fluorescence-microscopy
#11
Daijiro Kobayashi, Atsushi Shibata, Takahiro Oike, Takashi Nakano
Research on ionizing radiation (IR)-induced clonogenic cell death is important for understanding the effect of IR on malignant tumors and normal tissues. Here, we describe a quick and cost-effective one-step assay for simultaneously assessing the major modes of clonogenic cell death induced by IR, i.e., apoptosis, mitotic catastrophe, and cellular senescence. In this method, cells grown on a cover slip are irradiated with X-rays and stained with 4',6-diamidino-2-phenylindole dihydrochloride (DAPI). Using fluorescence microscopy, apoptosis, mitotic catastrophe, and cellular senescence are identified based on the characteristic morphologies of the DAPI-stained nuclei...
October 23, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29145865/the-endonuclease-eepd1-mediates-synthetic-lethality-in-rad52-depleted-brca1-mutant-breast-cancer-cells
#12
Robert Hromas, Hyun-Suk Kim, Gurjit Sidhu, Elizabeth Williamson, Aruna Jaiswal, Taylor A Totterdale, Jocelyn Nole, Suk-Hee Lee, Jac A Nickoloff, Kimi Y Kong
BACKGROUND: Proper repair and restart of stressed replication forks requires intact homologous recombination (HR). HR at stressed replication forks can be initiated by the 5' endonuclease EEPD1, which cleaves the stalled replication fork. Inherited or acquired defects in HR, such as mutations in breast cancer susceptibility protein-1 (BRCA1) or BRCA2, predispose to cancer, including breast and ovarian cancers. In order for these HR-deficient tumor cells to proliferate, they become addicted to a bypass replication fork repair pathway mediated by radiation repair protein 52 (RAD52)...
November 16, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/29142903/beti-induction-of-mitotic-catastrophe-towing-the-lin9
#13
EDITORIAL
Sylvia S Gayle, Jennifer M Sahni, Ruth A Keri
No abstract text is available yet for this article.
September 2017: Oncoscience
https://www.readbyqxmd.com/read/29115590/overexpression-of-lamin-b1-induces-mitotic-catastrophe-in-colon-cancer-lovo-cells-and-is-associated-with-worse-clinical-outcomes
#14
Magdalena Izdebska, Maciej Gagat, Alina Grzanka
Lamins are the major components of the nuclear lamina and play important roles in many cellular processes. The role of lamins in cancer development and progression is still unclear but it is known that reduced expression of lamin B1 has been observed in colon cancer. Thus, the aim of the present study was to elucidate the influence of LMNB1 upregulation on colon cancer cell line after treatment with 5-FU. The results indicate, that overexpression of LMNB1 induced dose-dependent cell death mainly by mitotic catastrophe pathway...
November 1, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/29109414/involvement-of-autophagy-in-the-outcome-of-mitotic-catastrophe
#15
Irina V Sorokina, Tatiana V Denisenko, Gabriela Imreh, Pyotr A Tyurin-Kuzmin, Vitaliy O Kaminskyy, Vladimir Gogvadze, Boris Zhivotovsky
Evading cell death is a major driving force for tumor progression that is one of the main problems in current cancer research. Mitotic catastrophe (MC) represents attractive platform compromising tumor resistance to current therapeutic modalities. MC appeared as onco-suppressive mechanism and is defined as a stage driving the cell to an irreversible destiny, i.e. cell death via apoptosis or necrosis. Our study highlights that MC induction in colorectal carcinoma cell lines ultimately leads to the autophagy followed by apoptosis...
November 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29107018/flubendazole-induces-mitotic-catastrophe-and-apoptosis-in-melanoma-cells
#16
K Čáňová, L Rozkydalová, D Vokurková, E Rudolf
Flubendazole (FLU) is a widely used anthelmintic drug belonging to benzimidazole group. Recently, several studies have been published demonstrating its potential to inhibit growth of various tumor cells including those derived from colorectal cancer, breast cancer or leukemia via several mechanisms. In the present study we have investigated cytotoxic effects of FLU on malignant melanoma using A-375, BOWES and RPMI-7951 cell lines representing diverse melanoma molecular types. In all three cell lines, FLU inhibited cell growth and proliferation and disrupted microtubule structure and function which was accompanied by dramatic changes in cellular morphology...
October 26, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/29092660/identification-of-dise-inducing-shrnas-by-monitoring-cellular-responses
#17
Monal Patel, Marcus E Peter
Off-target effects (OTE) are an undesired side effect of RNA interference (RNAi) caused by partial complementarity between the targeting siRNA and mRNAs other than the gene to be silenced. The death receptor CD95 and its ligand CD95L contain multiple sequences that when expressed as either si- or shRNAs kill cancer cells through a defined OTE that targets critical survival genes. Death induced by survival gene elimination (DISE) is characterized by specific morphological changes such as elongated cell shapes, senescence-like enlarged cells, appearance of large intracellular vesicles, release of mitochondrial ROS followed by activation of caspase-2, and induction of a necrotic form of mitotic catastrophe...
November 1, 2017: Cell Cycle
https://www.readbyqxmd.com/read/29040814/inhibiting-polo-like-kinase-1-plk1-enhances-radiosensitization-via-modulating-dna-repair-proteins-in-non-small-cell-lung-cancer
#18
Da Yao, Peigui Gu, Youyu Wang, Weibin Luo, Huiliang Chi, Jianjun Ge, Youhui Qian
To assure the faithful chromosome segregation, cells make use of the spindle assembly checkpoint (SAC), which can be activated in aneuploidy cancer cells. In this study, the efficacies of inhibiting Polo-like kinase 1 (PLK1) on the radiosensitization of non-small cell lung cancer (NSCLC) cells were studied. Clonogenic survival assay was performed to identify the effects of the PLK1 inhibitor on radiosensitivity within NSCLC cells. Mitotic catastrophe assessment was used to measure the cell death and γH2AX foci were utilized to assess the DNA double-strand breaks (DSB)...
October 17, 2017: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
https://www.readbyqxmd.com/read/29016926/activation-of-wee1-confers-resistance-to-pi3k-inhibition-in-glioblastoma
#19
Shaofang Wu, Shuzhen Wang, Feng Gao, Luyuan Li, Siyuan Zheng, W K Alfred Yung, Dimpy Koul
Background: Oncogenic activation of phosphatidylinositol-3 kinase (PI3K) signaling plays a pivotal role in the development of glioblastoma (GBM). However, pharmacological inhibition of PI3K has so far not been therapeutically successful due to adaptive resistance through a rapid rewiring of cancer cell signaling. Here we identified that WEE1 is activated after transient exposure to PI3K inhibition and confers resistance to PI3K inhibition in GBM. Methods: Patient-derived glioma-initiating cells and established GBM cells were treated with PI3K inhibitor or WEE1 inhibitor alone or in combination, and cell proliferation was evaluated by CellTiter-Blue assay...
July 7, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28993779/natural-killer-cell-response-to-chemotherapy-stressed-cancer-cells-role-in-tumor-immunosurveillance
#20
REVIEW
Alessandra Zingoni, Cinzia Fionda, Cristiana Borrelli, Marco Cippitelli, Angela Santoni, Alessandra Soriani
Natural killer (NK) cells are innate cytotoxic lymphoid cells that actively prevent neoplastic development, growth, and metastatic dissemination in a process called cancer immunosurveillance. An equilibrium between immune control and tumor growth is maintained as long as cancer cells evade immunosurveillance. Therapies designed to kill cancer cells and to simultaneously sustain host antitumor immunity are an appealing strategy to control tumor growth. Several chemotherapeutic agents, depending on which drugs and doses are used, give rise to DNA damage and cancer cell death by means of apoptosis, immunogenic cell death, or other forms of non-apoptotic death (i...
2017: Frontiers in Immunology
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