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Sofie Martens, Vera Goossens, Lars Devisscher, Sam Hofmans, Polien Claeys, Marnik Vuylsteke, Nozomi Takahashi, Koen Augustyns, Peter Vandenabeele
The Aurora kinase family (Aurora A, B and C) are crucial regulators of several mitotic events, including cytokinesis. Increased expression of these kinases is associated with tumorigenesis and several compounds targeting Aurora kinase are under evaluation in clinical trials (a.o. AT9283, AZD1152, Danusertib, MLN8054). Here, we demonstrate that the pan-Aurora kinase inhibitor Tozasertib (VX-680 and MK-0457) not only causes cytokinesis defects through Aurora kinase inhibition, but is also a potent inhibitor of necroptosis, a cell death process regulated and executed by the RIPK1, RIPK3 and MLKL signalling axis...
February 12, 2018: Cell Death & Disease
Anna S Nikonova, Alexander Y Deneka, Anna A Kiseleva, Vladislav Korobeynikov, Anna Gaponova, Ilya G Serebriiskii, Meghan C Kopp, Harvey H Hensley, Tamina N Seeger-Nukpezah, Stefan Somlo, David A Proia, Erica A Golemis
Autosomal-dominant polycystic kidney disease (ADPKD) is associated with progressive formation of renal cysts, kidney enlargement, hypertension, and typically end-stage renal disease. In ADPKD, inherited mutations disrupt function of the polycystins (encoded by PKD1 and PKD2), thus causing loss of a cyst-repressive signal emanating from the renal cilium. Genetic studies have suggested ciliary maintenance is essential for ADPKD pathogenesis. Heat shock protein 90 (HSP90) clients include multiple proteins linked to ciliary maintenance...
January 10, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Andreas Ritter, Alexandra Friemel, Nina-Naomi Kreis, Samira Catharina Hoock, Susanne Roth, Ulrikke Kielland-Kaisen, Dörthe Brüggmann, Christine Solbach, Frank Louwen, Juping Yuan
Adipose-derived mesenchymal stem cells (ASCs) have crucial functions, but their roles in obesity are not well defined. We show here that ASCs from obese individuals have defective primary cilia, which are shortened and unable to properly respond to stimuli. Impaired cilia compromise ASC functionalities. Exposure to obesity-related hypoxia and cytokines shortens cilia of lean ASCs. Like obese ASCs, lean ASCs treated with interleukin-6 are deficient in the Hedgehog pathway, and their differentiation capability is associated with increased ciliary disassembly genes like AURKA...
January 26, 2018: Stem Cell Reports
Seiga Ohmine, Jeffrey L Salisbury, James Ingle, Giuseppe Pettinato, Candace L Haddox, Tufia Haddad, Evanthia Galanis, Yasuhiro Ikeda, Antonino B D'assoro
The discovery of human induced pluripotent stem cells (hiPSCs) is a promising advancement in the field of regenerative and personalized medicine. Expression of SOX2, KLF4, OCT4 and MYC transcription factors induces the nuclear reprogramming of somatic cells into hiPSCs that share striking similarities with human embryonic stem cells (hESCs). However, several studies have demonstrated that hESCs and hiPSCs could lead to teratoma formation in vivo, thus limiting their current clinical applications. Aberrant cell cycle regulation of hESCs is linked to centrosome amplification, which may account, for their enhanced chromosomal instability (CIN), and thus increase their tumorigenicity...
January 31, 2018: Oncology Reports
Alessandro Antonelli, Carlotta Palumbo, Alessandro Veccia, Salvatore Grisanti, Luca Triggiani, Stefania Zamboni, Maria Furlan, Claudio Simeone, Stefano Magrini, Alfredo Berruti
INTRODUCTION: Androgen-deprivation therapy (ADT) administered in neoadjuvant setting before radical prostatectomy (RP) represents an ideal in vivo human model to test the efficacy of hormonal treatments in prostate cancer (PCa). This review summarizes the findings from published studies specifically focused on the biological effects of ADT assessed on specimens from RP. The aim is to provide a base of knowledge that might be used to design future studies on neoadjuvant therapy for PCa...
February 1, 2018: Minerva Urologica e Nefrologica, the Italian Journal of Urology and Nephrology
Xu Zhang, Yan Feng, Xin-Yu Wang, Ya-Nan Zhang, Chun-Nv Yuan, Song-Fa Zhang, Yuan-Ming Shen, Yun-Feng Fu, Cai-Yun Zhou, Xiao Li, Xiao-Dong Cheng, Wei-Guo Lu, Xing Xie
Paclitaxel is widely used as a first-line chemotherapeutic drug for patients with ovarian cancer and other solid cancers, but drug resistance occurs frequently, resulting in ovarian cancer still presenting as the highest lethality among all gynecological tumors. Here, using DIGE quantitative proteomics, we identified UBC13 as down-regulated in paclitaxel-resistant ovarian cancer cells, and it was further revealed by immunohistochemical staining that UBC13 low-expression was associated with poorer prognosis and shorter survival of the patients...
January 24, 2018: Cell Death & Disease
Liang Long, Yu Luo, Zhi-Jie Hou, Hua-Juan Ma, Zi-Jie Long, Zheng-Chao Tu, Lin-Jie Huang, Quentin Liu, Gui Lu
The inhibition of the members of aurora kinase family using ATP-competitive small molecules is an effective method for anticancer therapeutics. Based on our previous work, we synthesized 12 new N-trisubstituted pyrimidine derivatives and evaluated their biological activities and stabilities. Among them, compound 11j showed the best inhibition against aurora A kinase (IC50 = 7.1 nM), human leukemia cell line U937 (IC50 = 12.2 nM) and the growth of U937 xenograft tumors in vivo. By the flow cytometry and immunofluorescence analysis of U937, we found that compound 11j can induced polyploidy formation including (4N, 8N and 16N) and induce defects in both chromosome alignment and spindle formation...
January 11, 2018: European Journal of Medicinal Chemistry
Ashraf N E Hamed, Roland Schmitz, Anja Bergermann, Frank Totzke, Michael Kubbutat, Werner E G Müller, Diaa T A Youssef, Mokhtar M Bishr, Mohamed S Kamel, RuAngelie Edrada-Ebel, Wim Wätjen, Peter Proksch
Fifteen pyrrole alkaloids were isolated from the Red Sea marine sponge Stylissa carteri and investigated for their biological activities. Four of them were dibrominated [(+) dibromophakelline, Z-3-bromohymenialdisine, (±) ageliferin and 3,4-dibromo-1H-pyrrole-2-carbamide], nine compounds were monobrominated [(-) clathramide C, agelongine, (+) manzacidin A, (-) 3-bromomanzacidin D, Z-spongiacidin D, Z-hymenialdisine, 2-debromostevensine, 2-bromoaldisine and 4-bromo-1H-pyrrole-2-carbamide)] and finally, two compounds were non-brominated derivatives viz...
January 20, 2018: Zeitschrift Für Naturforschung. C, A Journal of Biosciences
Sriyash Mangal, Jennifer Sacher, Taekyung Kim, Daniel Sampaio Osório, Fumio Motegi, Ana Xavier Carvalho, Karen Oegema, Esther Zanin
During cytokinesis, a signal from the central spindle that forms between the separating anaphase chromosomes promotes the accumulation of contractile ring components at the cell equator, while a signal from the centrosomal microtubule asters inhibits accumulation of contractile ring components at the cell poles. However, the molecular identity of the inhibitory signal has remained unknown. To identify molecular components of the aster-based inhibitory signal, we developed a means to monitor the removal of contractile ring proteins from the polar cortex after anaphase onset...
January 8, 2018: Journal of Cell Biology
Yuan-Yuan Shang, Ming Yao, Zhi-Wei Zhou, Jian-Cui, Li-Xia, Rong-Ying Hu, Ying-Yao Yu, Qiong-Gao, Biao-Yang, Yu-Xi Liu, Jie Dang, Shu-Feng Zhou, Nan-Yu
We investigated the efficacy of Alisertib (ALS), a selective Aurora kinase A (AURKA) inhibitor, in melanoma. We found that ALS exerts anti-proliferative, pro-apoptotic, and pro-autophagic effects on A375 and skmel-5 melanoma cells by inhibiting p38 MAPK signaling. SB202190, a p38 MAPK-selective inhibitor, enhanced ALS-induced apoptosis and autophagy in both cell lines. ALS induced cell cycle arrest in melanoma cells through activation of the p53/p21/cyclin B1 pathway. Knockdown of p38 MAPK enhanced ALS-induced apoptosis and reduced ALS-induced autophagy...
December 5, 2017: Oncotarget
Tufia C Haddad, Antonino D'Assoro, Vera Suman, Mateusz Opyrchal, Prema Peethambaram, Minetta C Liu, Matthew P Goetz, James N Ingle
PURPOSE: In estrogen receptor-positive (ER+) breast cancer models, activation of Aurora A kinase (AURKA) is associated with downregulation of ERα expression and resistance to endocrine therapy. Alisertib is an oral selective inhibitor of AURKA. The primary objectives of this phase I trial were to determine the recommended phase II dose (RP2D) and evaluate the toxicities and clinical activity of alisertib combined with fulvestrant in patients with ER+ metastatic breast cancer (MBC). METHODS: In this standard 3 + 3 dose-escalation phase I study, postmenopausal patients with endocrine-resistant, ER+ MBC previously treated with endocrine therapy were assigned to one of two dose levels of alisertib (40 or 50 mg) in combination with fixed-dose fulvestrant...
December 30, 2017: Breast Cancer Research and Treatment
Gabriele Büchel, Anne Carstensen, Ka-Yan Mak, Isabelle Roeschert, Eoin Leen, Olga Sumara, Julia Hofstetter, Steffi Herold, Jacqueline Kalb, Apoorva Baluapuri, Evon Poon, Colin Kwok, Louis Chesler, Hans Michael Maric, David S Rickman, Elmar Wolf, Richard Bayliss, Susanne Walz, Martin Eilers
MYC proteins bind globally to active promoters and promote transcriptional elongation by RNA polymerase II (Pol II). To identify effector proteins that mediate this function, we performed mass spectrometry on N-MYC complexes in neuroblastoma cells. The analysis shows that N-MYC forms complexes with TFIIIC, TOP2A, and RAD21, a subunit of cohesin. N-MYC and TFIIIC bind to overlapping sites in thousands of Pol II promoters and intergenic regions. TFIIIC promotes association of RAD21 with N-MYC target sites and is required for N-MYC-dependent promoter escape and pause release of Pol II...
December 19, 2017: Cell Reports
Young-Jun Choi, Hyemin Kim, Ji-Woo Kim, Chang-Woo Song, Dae-Sung Kim, Seokjoo Yoon, Han-Jin Park
During liver development, nonpolarized hepatic progenitor cells differentiate into mature hepatocytes with distinct polarity. This polarity is essential for maintaining the intrinsic properties of hepatocytes. The balance between the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) plays a decisive role in differentiation of polarized hepatocytes. In this study, we found that phthalazinone pyrazole (PP), a selective inhibitor of Aurora-A kinase (Aurora-A), suppressed the EMT during the differentiation of hepatocyte-like cells (HLCs) from human embryonic stem cells...
December 13, 2017: Stem Cell Reviews
Byung Ho Lee, Francoise Schwager, Patrick Meraldi, Monica Gotta
Spindle orientation determines the axis of division and is crucial for cell fate, tissue morphogenesis, and the development of an organism. In animal cells, spindle orientation is regulated by the conserved Gαi-LGN-NuMA complex, which targets the force generator dynein-dynactin to the cortex. In this study, we show that p37/UBXN2B, a cofactor of the p97 AAA ATPase, regulates spindle orientation in mammalian cells by limiting the levels of cortical NuMA. p37 controls cortical NuMA levels via the phosphatase PP1 and its regulatory subunit Repo-Man, but it acts independently of Gαi, the kinase Aurora A, and the phosphatase PP2A...
December 8, 2017: Journal of Cell Biology
Mateusz Opyrchal, Malgorzata Gil, Jeffrey L Salisbury, Mathew P Goetz, Vera Suman, Amy Degnim, James McCubrey, Tufia Haddad, Ianko Iankov, Chenye B Kurokawa, Nicole Shumacher, James N Ingle, Evanthia Galanis, Antonino B D'Assoro
Although the majority of breast cancers initially respond to the cytotoxic effects of chemotherapeutic agents, most breast cancer patients experience tumor relapse and ultimately die because of drug resistance. Breast cancer cells undergoing epithelial to mesenchymal transition (EMT) acquire a CD44+/CD24-/ALDH1+ cancer stem cell-like phenotype characterized by an increased capacity for tumor self-renewal, intrinsic drug resistance and high proclivity to develop distant metastases. We uncovered in human breast tumor xenografts a novel non-mitotic role of Aurora-A kinase in promoting breast cancer metastases through activation of EMT and expansion of breast tumor initiating cells (BTICs)...
October 31, 2017: Oncotarget
Anne E Lykkesfeldt, Benedikte R Iversen, Maj-Britt Jensen, Bent Ejlertsen, Anita Giobbie-Hurder, Birgit E Reiter, Tove Kirkegaard, Birgitte B Rasmussen
BACKGROUND: Cell culture studies have disclosed that the mitotic Aurora kinase A is causally involved in both tamoxifen and aromatase inhibitor resistant cell growth and thus may be a potential new marker for endocrine resistance in the clinical setting. MATERIAL AND METHODS: Archival tumor tissue was available from 1323 Danish patients with estrogen receptor (ER) positive primary breast cancer, who participated in the Breast International Group (BIG) 1-98 trial, comparing treatment with tamoxifen and letrozole and both in a sequence...
December 4, 2017: Acta Oncologica
Keith F DeLuca, Amanda Meppelink, Amanda J Broad, Jeanne E Mick, Olve B Peersen, Sibel Pektas, Susanne M A Lens, Jennifer G DeLuca
Precise regulation of kinetochore-microtubule attachments is essential for successful chromosome segregation. Central to this regulation is Aurora B kinase, which phosphorylates kinetochore substrates to promote microtubule turnover. A critical target of Aurora B is the N-terminal "tail" domain of Hec1, which is a component of the NDC80 complex, a force-transducing link between kinetochores and microtubules. Although Aurora B is regarded as the "master regulator" of kinetochore-microtubule attachment, other mitotic kinases likely contribute to Hec1 phosphorylation...
November 29, 2017: Journal of Cell Biology
Lilian Kabeche, Hai Dang Nguyen, Remi Buisson, Lee Zou
The ATR kinase is crucial for DNA damage and replication stress responses. Here, we describe a surprising role of ATR in mitosis. Acute inhibition or degradation of ATR in mitosis induces whole-chromosome missegregation. The effect of ATR ablation is not due to altered CDK1 activity, DNA damage responses, or unscheduled DNA synthesis, but to loss of an ATR function at centromeres. In mitosis, ATR localizes to centromeres through Aurora A-regulated association with CENP-F, allowing ATR to engage RPA-coated centromeric R loops...
November 23, 2017: Science
Nicole DeVaul, Katerina Koloustroubis, Rong Wang, Ann O Sperry
BACKGROUND: The primary cilium is an extension of the cell membrane that encloses a microtubule-based axoneme. Primary cilia are essential for transmission of environmental cues that determine cell fate. Disruption of primary cilia function is the molecular basis of numerous developmental disorders. Despite their biological importance, the mechanisms governing their assembly and disassembly are just beginning to be understood. Cilia growth and disassembly are essential events when cells exit and reenter into the cell cycle...
November 15, 2017: BMC Cell Biology
Li-Li Wang, Xiao-Han Jin, Mu-Yan Cai, Hai-Gang Li, Jie-Wei Chen, Feng-Wei Wang, Chen-Yuan Wang, Wei-Wei Hu, Fang Liu, Dan Xie
AGBL2 has been reported to catalyze α-tubulin detyrosination, by which it promotes tumorigenesis and cancer progression. However, its potential role in the pathogenesis of hepatocellular carcinoma (HCC) has not been revealed yet. In the present study, AGBL2 was frequently found being overexpressed in HCC tissues and cell lines. In a large cohort of clinical HCC tissues, high expression of AGBL2 was positively associated with tumor size, tumor multiplicity and advanced clinical stage (p < 0.05), and it was an independent prognostic factor for HCC patients...
February 1, 2018: Cancer Letters
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