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Mitotic catastrophe

Elzbieta Pawlowska, Joanna Szczepanska, Magdalena Szatkowska, Janusz Blasiak
Autophagy, cellular senescence, programmed cell death and necrosis are key responses of a cell facing a stress. These effects are partly interconnected, but regulation of their mutual interactions is not completely clear. That regulation seems to be especially important in cancer cells, which have their own program of development and demand more nutrition and energy than normal cells. Glioblastoma multiforme (GBM) belongs to the most aggressive and most difficult to cure cancers, so studies on its pathogenesis and new therapeutic strategies are justified...
March 17, 2018: International Journal of Molecular Sciences
Maeva Dufies, Damien Ambrosetti, Sonia Boulakirba, Anne Calleja, Coline Savy, Nathan Furstoss, Marwa Zerhouni, Julien Parola, Lazaro Aira-Diaz, Sandrine Marchetti, Francois Orange, Sandra Lacas-Gervais, Frederic Luciano, Arnaud Jacquel, Guillaume Robert, Gilles Pagès, Patrick Auberger
Polo-like kinases (Plks) define a highly conserved family of Ser/Thr kinases with crucial roles in the regulation of cell division. Here we show that Plk1 is cleaved by caspase 3, but not by other caspases in different hematopoietic cell lines treated with competitive inhibitors of the ATP-binding pocket of Plk1. Intriguingly, Plk1 was not cleaved in cells treated with Rigosertib, a non-competitive inhibitor of Plk1, suggesting that binding of the inhibitor to the ATP binding pocket of Plk1 triggers a conformational change and unmasks a cryptic caspase 3 cleavage site on the protein...
February 16, 2018: Oncotarget
Anja Müller, Bernd Gillissen, Antje Richter, Anja Richter, Cindrilla Chumduri, Peter T Daniel, Christian W Scholz
Constitutive signaling of PI3K/Akt/mTOR plays a prominent role in malignant transformation and progression of B-cell non-Hodgkin lymphomas (B-NHL) underscoring the need for PI3K targeted therapies. The pan-class I PI3-kinase inhibitor BKM120 has shown preclinical activity in distinct malignancies and is currently tested in clinical trials. Intratumor heterogeneity is an intrinsic property of cancers that contributes to drug resistance and tumor recurrence. Here, we demonstrate that inhibition of PI3-kinases by BKM120 attenuates growth and survival of B-NHL cell lines by inducing mitotic arrest with subsequent induction of intrinsic apoptosis...
March 7, 2018: Cell Death & Disease
Chen Qi, Xin Wang, Zhirong Shen, She Chen, Hong Yu, Noelle Williams, Gelin Wang
The commonly used antimitotic chemotherapeutic agents such as taxol and vinblastine arrest cell cycle progression by disrupting mitotic spindles, and cause cancer cells to undergo apoptosis through 'mitotic catastrophe'. The molecular mechanisms by which these drugs induce apoptosis and their relevance to clinical efficacy are not known. Facilitated by a new spindle poison diazonamide, we found that apoptosis induced by these agents requires death receptor 3 (DR3). Mitotic arrest by these agents induces lysosome-dependent secretion of the DR3 ligand, TL1A...
March 1, 2018: Cell Research
Zhaoshi Bai, Meiqi Gao, Xiaobo Xu, Huijuan Zhang, Jingwen Xu, Qi Guan, Qing Wang, Jianan Du, Zhengqiang Li, Daiying Zuo, Weige Zhang, Yingliang Wu
OBJECTIVES: Our previous in vitro study showed that 5-(3, 4, 5-trimethoxybenzoyl)-4-methyl-2-(p-tolyl) imidazol (BZML) is a novel colchicine binding site inhibitor with potent anti-cancer activity against apoptosis resistance in A549/Taxol cells through mitotic catastrophe (MC). However, the mechanisms underlying apoptosis resistance in A549/Taxol cells remain unknown. To clarify these mechanisms, in the present study, we investigated the molecular mechanisms of apoptosis and autophagy, which are closely associated with MC in BZML-treated A549 and A549/Taxol cells...
March 1, 2018: Cell Proliferation
Anja Göder, Claudia Emmerich, Teodora Nikolova, Nicole Kiweler, Maria Schreiber, Toni Kühl, Diana Imhof, Markus Christmann, Thorsten Heinzel, Günter Schneider, Oliver H Krämer
Checkpoint kinases sense replicative stress to prevent DNA damage. Here we show that the histone deacetylases HDAC1/HDAC2 sustain the phosphorylation of the checkpoint kinases ATM, CHK1 and CHK2, activity of the cell cycle gatekeeper kinases WEE1 and CDK1, and induction of the tumour suppressor p53 in response to stalled DNA replication. Consequently, HDAC inhibition upon replicative stress promotes mitotic catastrophe. Mechanistically, HDAC1 and HDAC2 suppress the expression of PPP2R3A/PR130, a regulatory subunit of the trimeric serine/threonine phosphatase 2 (PP2A)...
February 22, 2018: Nature Communications
Rajvee Shah Punatar, Stephen C West
Holliday junctions provide a covalent link between recombining DNA molecules and need to be removed prior to chromosome segregation at mitosis. Defects in their resolution lead to mitotic catastrophe, characterized by the formation of DNA breaks and chromosome aberrations. Enzymes that resolve recombination intermediates have been identified in all forms of life, from bacteriophage, to bacteria, yeast, and humans. In higher eukaryotes, Holliday junctions are resolved by GEN1, a nuclease that is mechanistically similar to the prototypic resolvase Escherichia coli RuvC, and by the SMX trinuclease complex...
2018: Methods in Enzymology
Ewelina Zielinska, Agata Zauszkiewicz-Pawlak, Michal Wojcik, Iwona Inkielewicz-Stepniak
Pancreatic ductal adenocarcinoma, with the high resistance to chemotherapeutic agents, remains the fourth leading cause of cancer-death in the world. Due to the wide range of biological activity and unique properties, silver nanoparticles (AgNPs) are indicated as agents with potential to overcome barriers involved in chemotherapy failure. Therefore, in our study we decided to assess the ability of AgNPs to kill pancreatic cancer cells, and then to identify the molecular mechanism underlying this effect. Moreover, we evaluated the cytotoxicity of AgNPs against non-tumor cell of the same tissue (hTERT-HPNE cells) for comparison...
January 12, 2018: Oncotarget
Yeon Woo Song, Yoongho Lim, Somi Kim Cho
The natural product 2,4-di-tert-butylphenol (DTBP) has a wide spectrum of biological functions, including anticancer activities, although the underlying mechanisms are poorly understood. Here, we found that DTBP induces senescence in human gastric adenocarcinoma AGS cells as evidenced by upregulation of p21 and Rb and increased β-galactosidase activity. DTBP also induces mitotic catastrophe and generates multinucleated cells, which is accompanied by an increase in the proportion of polymerized tubulin, possibly caused by inhibition of HDAC6 enzyme activity...
February 7, 2018: Biochimica et Biophysica Acta
Kaizhao Zhang, Xiaotong Tan, Ying Li, Guan Liang, Zhangyong Ning, Yongjiang Ma, Yugu Li
Zearalenone (ZEA) was a mycotoxin biosynthesized by a variety of Fusarium fungi via a polypeptide pathway. ZEA has significant toxic reaction on immune cells. Thymic epithelial cells (TECs) as a crucial constituent of thymic stroma can provide unique microenvironment for thymocyte maturation, but the mechanism of ZEA affecting the TECs is poorly understood. The basic data about gene expression differences for the ZEA on thymic epithelial cell line 1 (MTEC1) will help us to elucidate this mechanism. Here, cell viability and proliferation assay and transcriptome sequencing on MTEC1 treated with ZEA were performed...
February 6, 2018: Ecotoxicology and Environmental Safety
Silvia Pietrobono, Roberta Santini, Sinforosa Gagliardi, Francesca Dapporto, David Colecchia, Mario Chiariello, Cosima Leone, Massimo Valoti, Fabrizio Manetti, Elena Petricci, Maurizio Taddei, Barbara Stecca
Aberrant activation of the Hedgehog (HH) signaling is a critical driver in tumorigenesis. The Smoothened (SMO) receptor is one of the major upstream transducers of the HH pathway and a target for the development of anticancer agents. The SMO inhibitor Vismodegib (GDC-0449/Erivedge) has been approved for treatment of basal cell carcinoma. However, the emergence of resistance during Vismodegib treatment and the occurrence of numerous side effects limit its use. Our group has recently discovered and developed novel and potent SMO inhibitors based on acylguanidine or acylthiourea scaffolds...
February 2, 2018: Cell Death & Disease
Lorenzo Galluzzi, Ilio Vitale, Stuart A Aaronson, John M Abrams, Dieter Adam, Patrizia Agostinis, Emad S Alnemri, Lucia Altucci, Ivano Amelio, David W Andrews, Margherita Annicchiarico-Petruzzelli, Alexey V Antonov, Eli Arama, Eric H Baehrecke, Nickolai A Barlev, Nicolas G Bazan, Francesca Bernassola, Mathieu J M Bertrand, Katiuscia Bianchi, Mikhail V Blagosklonny, Klas Blomgren, Christoph Borner, Patricia Boya, Catherine Brenner, Michelangelo Campanella, Eleonora Candi, Didac Carmona-Gutierrez, Francesco Cecconi, Francis K-M Chan, Navdeep S Chandel, Emily H Cheng, Jerry E Chipuk, John A Cidlowski, Aaron Ciechanover, Gerald M Cohen, Marcus Conrad, Juan R Cubillos-Ruiz, Peter E Czabotar, Vincenzo D'Angiolella, Ted M Dawson, Valina L Dawson, Vincenzo De Laurenzi, Ruggero De Maria, Klaus-Michael Debatin, Ralph J DeBerardinis, Mohanish Deshmukh, Nicola Di Daniele, Francesco Di Virgilio, Vishva M Dixit, Scott J Dixon, Colin S Duckett, Brian D Dynlacht, Wafik S El-Deiry, John W Elrod, Gian Maria Fimia, Simone Fulda, Ana J García-Sáez, Abhishek D Garg, Carmen Garrido, Evripidis Gavathiotis, Pierre Golstein, Eyal Gottlieb, Douglas R Green, Lloyd A Greene, Hinrich Gronemeyer, Atan Gross, Gyorgy Hajnoczky, J Marie Hardwick, Isaac S Harris, Michael O Hengartner, Claudio Hetz, Hidenori Ichijo, Marja Jäättelä, Bertrand Joseph, Philipp J Jost, Philippe P Juin, William J Kaiser, Michael Karin, Thomas Kaufmann, Oliver Kepp, Adi Kimchi, Richard N Kitsis, Daniel J Klionsky, Richard A Knight, Sharad Kumar, Sam W Lee, John J Lemasters, Beth Levine, Andreas Linkermann, Stuart A Lipton, Richard A Lockshin, Carlos López-Otín, Scott W Lowe, Tom Luedde, Enrico Lugli, Marion MacFarlane, Frank Madeo, Michal Malewicz, Walter Malorni, Gwenola Manic, Jean-Christophe Marine, Seamus J Martin, Jean-Claude Martinou, Jan Paul Medema, Patrick Mehlen, Pascal Meier, Sonia Melino, Edward A Miao, Jeffery D Molkentin, Ute M Moll, Cristina Muñoz-Pinedo, Shigekazu Nagata, Gabriel Nuñez, Andrew Oberst, Moshe Oren, Michael Overholtzer, Michele Pagano, Theocharis Panaretakis, Manolis Pasparakis, Josef M Penninger, David M Pereira, Shazib Pervaiz, Marcus E Peter, Mauro Piacentini, Paolo Pinton, Jochen H M Prehn, Hamsa Puthalakath, Gabriel A Rabinovich, Markus Rehm, Rosario Rizzuto, Cecilia M P Rodrigues, David C Rubinsztein, Thomas Rudel, Kevin M Ryan, Emre Sayan, Luca Scorrano, Feng Shao, Yufang Shi, John Silke, Hans-Uwe Simon, Antonella Sistigu, Brent R Stockwell, Andreas Strasser, Gyorgy Szabadkai, Stephen W G Tait, Daolin Tang, Nektarios Tavernarakis, Andrew Thorburn, Yoshihide Tsujimoto, Boris Turk, Tom Vanden Berghe, Peter Vandenabeele, Matthew G Vander Heiden, Andreas Villunger, Herbert W Virgin, Karen H Vousden, Domagoj Vucic, Erwin F Wagner, Henning Walczak, David Wallach, Ying Wang, James A Wells, Will Wood, Junying Yuan, Zahra Zakeri, Boris Zhivotovsky, Laurence Zitvogel, Gerry Melino, Guido Kroemer
Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes...
January 23, 2018: Cell Death and Differentiation
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
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
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 bioriented, 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...
February 15, 2018: Molecular Biology of the Cell
Xiaoguang Wang, Zhangguo Chen, Ameet K Mishra, Alexa Silva, Wenhua Ren, Zenggang Pan, Jing H Wang
Chemotherapeutic agents, e.g., cytarabine and doxorubicin, cause DNA damage. 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. 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 a Wee1 inhibitor. We found that cyclin A2/B1 upregulation appears to be an intrinsic programmed response to DNA damage; however, different types of B cells arrest in distinct phases of the cell cycle...
March 2018: Haematologica
Winson S 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...
February 28, 2018: Cancer Letters
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...
November 1, 2017: Genes & Development
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...
December 22, 2017: Journal of Natural Products
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 first mitotic spindle. Where these asters meet at the midplane, they assemble a disk-shaped interaction zone consisting of anti-parallel microtubule bundles coated with chromosome passenger complex (CPC) and centralspindlin that 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...
February 1, 2018: Molecular Biology of the Cell
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