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https://www.readbyqxmd.com/read/28337805/defining-the-anti-cancer-activity-of-tricarbonyl-rhenium-complexes-induction-of-g2-m-cell-cycle-arrest-and-blockade-of-aurora-a-kinase-phosphorylation
#1
Peter V Simpson, Ilaria Casari, Silvano Paternoster, Brian W Skelton, Marco Falasca, Massimiliano Massi
Rhenium and ruthenium complexes containing N-heterocylic carbene (NHC) ligands and conjugated to indomethacin were prepared. The anticancer properties were probed against pancreatic cell lines, revealing a remarkable activity of the rhenium fragment as anticancer agent. The ruthenium complexes were found to be inactive against the same pancreatic cancer cell lines, either alone or in conjugation with indomethacin. An in depth biological study revealed the origin of the anticancer properties of the rhenium tricarbonyl fragment, of which a complete elucidation had yet to be achieved...
March 23, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28298485/mcak-mediated-regulation-of-endothelial-cell-microtubule-dynamics-is-mechano-sensitive-to-myosin-ii-contractility
#2
Lauren D'Angelo, Nicole M Myer, Kenneth A Myers
Compliance and dimensionality mechanosensing, the processes by which cells sense the physical attributes of the extracellular environment (ECM), are known to drive cell branching and shape change largely through a myosin-II-mediated reorganization of the actin and microtubule (MT) cytoskeletons. Subcellular regulation of MT dynamics is spatially controlled through a Rac1-Aurora-A kinase pathway that locally inhibits the MT depolymerizing activity of MCAK, thereby promoting leading-edge MT growth and cell polarization...
March 15, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28284839/depletion-of-tumor-suppressor-kank1-induces-centrosomal-amplification-via-hyperactivation-of-rhoa
#3
Jun-Ichiro Suzuki, Badal Chandra Roy, Takunori Ogaeri, Naoto Kakinuma, Ryoiti Kiyama
Chromosome instability, frequently found in cancer cells, is caused by a deficiency in cell division, including centrosomal amplification and cytokinesis failure, and can result in abnormal chromosome content or aneuploidy. The small GTPase pathways have been implicated as important processes in cell division. We found that knockdown of a tumor suppressor protein Kank1 increases the number of cells with a micronucleus or bi-/multi-nuclei, which was likely caused by centrosomal amplification. Kank1 interacts with Daam1, known to bind to and activate a small GTPase, RhoA, in actin assembly...
March 8, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28269755/microrna-124-3p-affects-proliferation-migration-and-apoptosis-of-bladder-cancer-cells-through-targeting-aurka
#4
Qiuyue Yuan, Tingge Sun, Feng Ye, Weisheng Kong, Haofan Jin
OBJECTIVE: The aim of this study was to establish the relationship between miR-124-3p and Aurora A kinase (AURKA) in bladder cancer (BC). METHODS: The expressions of miR-124-3p and AURKA in BC tissues and cell lines were detected using RT-PCR and western blot. BC cells were transfected with miR-124-3p mimics and AURKA siRNA. After this cell proliferation, migration, cell cycle and apoptosis were measured using CCK-8, colony formation assay, wound healing assay and cytometry tests...
February 27, 2017: Cancer Biomarkers: Section A of Disease Markers
https://www.readbyqxmd.com/read/28269749/aurora-a-regulates-autophagy-through-the-akt-pathway-in-human-prostate-cancer
#5
Shiying Zhang, Jianye Li, Gaobiao Zhou, Dawei Mu, Jingmin Yan, Jizhang Xing, Zhiyong Yao, Haibo Sheng, Di Li, Chao Lv, Bin Sun, Quan Hong, Heqing Guo
BACKGROUND: Aurora A kinase is frequently overexpressed in a variety of tumor types, including the prostate. However, the function of Aurora A in autophagy in prostate cancer has not been investigated. Here, we aimed to study the functioning mechanism and autophagy associated signaling pathways of Aurora A in prostate cancer. METHODS: To investigate the biological function of Aurora A, down-regulation of Aurora A was performed followed by functional testing assays...
February 27, 2017: Cancer Biomarkers: Section A of Disease Markers
https://www.readbyqxmd.com/read/28260026/ube2c-induces-emt-through-wnt-%C3%AE-%C3%A2-catenin-and-pi3k-akt-signaling-pathways-by-regulating-phosphorylation-levels-of-aurora-a
#6
Rui Wang, Yue Song, Xi Liu, Qixue Wang, Yunfei Wang, Liwei Li, Chunsheng Kang, Qingyu Zhang
The ubiquitin-conjugating enzyme 2C (UBE2C) is the key component in the ubiquitin proteasome system (UPS) by partnering with the anaphase‑promoting complex (APC/C). A high UBE2C protein expression level has been reported in various types of human tumors. However, little is known about the precise mechanism by which UBE2C expression is downregulated in gastric cancer. We found in MGC‑803 and SGC‑7901 gastric cancer cells UBE2C‑deficient G2/M phase arrest in the cell cycle and subsequently decreased gastric adenocarcinoma tumorigenesis...
February 17, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28249963/cell-death-response-to-anti-mitotic-drug-treatment-in-cell-culture-mouse-tumor-model-and-the-clinic
#7
Jue Shi, Timothy J Mitchison
Anti-mitotic cancer drugs include classic microtubule-targeting drugs, such as taxanes and vinca alkaloids, and the newer spindle-targeting drugs, such as inhibitors of the motor protein, Kinesin-5 (aka KSP, Eg5, KIF11), and Aurora-A, Aurora-B and Polo-like kinases. Microtubule-targeting drugs are among the first line of chemotherapies for a wide spectrum of cancers, but patient responses vary greatly. We still lack understanding of how these drugs achieve a favorable therapeutic index, and why individual patient responses vary...
March 1, 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/28207834/a-cyclin-dependent-kinase-inhibitor-dinaciclib-in-preclinical-treatment-models-of-thyroid-cancer
#8
Shu-Fu Lin, Jen-Der Lin, Chuen Hsueh, Ting-Chao Chou, Richard J Wong
BACKGROUND: We explored the therapeutic effects of dinaciclib, a cyclin-dependent kinase (CDK) inhibitor, in the treatment of thyroid cancer. MATERIALS AND METHODS: Seven cell lines originating from three pathologic types of thyroid cancer (papillary, follicular and anaplastic) were studied. The cytotoxicity of dinaciclib was measured using a lactate dehydrogenase assay. The expression of proteins associated with cell cycle and apoptosis was assessed using Western blot analysis and immunofluorescence microscopy...
2017: PloS One
https://www.readbyqxmd.com/read/28205582/aurora-a-regulates-expression-of-ar-v7-in-models-of-castrate-resistant-prostate-cancer
#9
Dominic Jones, Martin Noble, Steve R Wedge, Craig N Robson, Luke Gaughan
Androgen receptor variants (AR-Vs) provide a mechanism of therapy evasion in castrate-resistant prostate cancer (CRPC), yet mechanisms of regulation remain largely unknown. Here we investigate the role of Aurora A kinase on AR-Vs in models of CRPC and show depletion of Aurora A reduces AR-V target gene expression. Importantly, knockdown of Aurora A reconfigures splicing of AR pre-mRNA to discriminately down-regulate synthesis of AR-V transcripts, including AR-V7, without effecting full-length AR mRNA; and as a consequence, AR-V-driven proliferation and survival of CRPC cells is markedly reduced...
February 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28202658/mechanisms-for-nonmitotic-activation-of-aurora-a-at-cilia
#10
REVIEW
Vladislav Korobeynikov, Alexander Y Deneka, Erica A Golemis
Overexpression of the Aurora kinase A (AURKA) is oncogenic in many tumors. Many studies of AURKA have focused on activities of this kinase in mitosis, and elucidated the mechanisms by which AURKA activity is induced at the G2/M boundary through interactions with proteins such as TPX2 and NEDD9. These studies have informed the development of small molecule inhibitors of AURKA, of which a number are currently under preclinical and clinical assessment. While the first activities defined for AURKA were its control of centrosomal maturation and organization of the mitotic spindle, an increasing number of studies over the past decade have recognized a separate biological function of AURKA, in controlling disassembly of the primary cilium, a small organelle protruding from the cell surface that serves as a signaling platform...
February 8, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28188792/recruitment-of-pp1-to-the-centrosomal-scaffold-protein-cep192
#11
Isha Nasa, Laura Trinkle-Mulcahy, P Douglas, Sibapriya Chaudhuri, S P Lees-Miller, Kyung S Lee, Greg B Moorhead
Centrosomal protein of 192 kDa (CEP192) is a scaffolding protein that recruits the mitotic protein kinases Aurora A and PLK1 to the centrosome. Here we demonstrate that CEP192 also recruits the type one protein phosphatase (PP1) via a highly conserved KHVTF docking motif. The threonine of the KHVTF motif is phosphorylated during mitosis and protein kinase inhibition studies suggest this to be a PLK1-dependent process.
February 8, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28188776/aurora-a-overexpression-aurka-is-driven-by-foxm1-and-mapk-erk-activation-in-melanoma-cells-harbouring-braf-or-nras-mutations-impact-on-melanoma-prognosis-and-therapy
#12
Joan Anton Puig-Butille, Antònia Vinyals, Josep R Ferreres, Paula Aguilera, Eduard Cabré, Gemma Tell-Martí, Joaquim Marcoval, Francesca Mateo, Luís Palomero, Celia Badenas, Josep M Piulats, Josep Malvehy, Miquel A Pujana, Susana Puig, Àngels Fabra
The cell cycle-related genes AURORA A and Forkhead box M1 (FOXM1) are overexpressed in melanoma. We show here that AURKA overexpression is associated with poor prognosis in three independent cohorts of melanoma patients and correlates with the presence of genomic amplification of AURKA locus and BRAF(V600E) mutation. AURKA overexpression may also be driven to increased promoter activation through elements such as ETS and FOXM1 found within the 5' proximal promoter region. Activated MAPK-ERK signalling pathway mediates robust AURKA promoter activation, thereby knockdown of BRAF(V600E) and ERK inhibition results in reduced AURKA transcription and expression...
February 7, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28178649/3-hydroxy-4-methoxy-%C3%AE-methyl-%C3%AE-nitrostyrene-inhibits-tumor-igenesis-in-colorectal-cancer-cells-through-ros-mediated-dna-damage-and-mitochondrial-dysfunction
#13
Chun-Hao Tsai, Amos C Hung, Yuan-Yin Chen, Ya-Wen Chiu, Pei-Wen Hsieh, Yi-Chen Lee, Yu-Han Su, Po-Chih Chang, Stephen Chu-Sung Hu, Shyng-Shiou F Yuan
The β-nitrostyrene family has been shown to suppress cell proliferation and induce apoptosis in types of various cancers. However, the mechanisms underlying the anticancer effects of β-nitrostyrenes in colorectal cancer remain poorly understood. In this study, we synthesized a β-nitrostyrene derivative, CYT-Rx20 (3'-hydroxy-4'-methoxy-β-methyl-β-nitrostyrene), and investigated its anticancer activities in human colorectal cancer cells both in vitro and in vivo. Our findings showed that treatment with CYT-Rx20 reduced cell viability and induced DNA damage in colorectal cancer cells...
February 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28178640/a-phase-i-ii-study-of-the-investigational-drug-alisertib-in-combination-with-abiraterone-and-prednisone-for-patients-with-metastatic-castration-resistant-prostate-cancer-progressing-on-abiraterone
#14
Jianqing Lin, Sheel A Patel, Ashwin R Sama, Jean H Hoffman-Censits, Brooke Kennedy, Deborah Kilpatrick, Zhong Ye, Hushan Yang, Zhaomei Mu, Benjamin Leiby, Nancy Lewis, Massimo Cristofanilli, William Kevin Kelly
LESSONS LEARNED: Patients with metastatic castration-resistant prostate cancer did not tolerate the combination of alisertib with abiraterone and prednisone.There was no clear signal indicating that adding alisertib might be beneficial for those patients progressing on abiraterone. BACKGROUND: We hypothesized that Aurora A kinase (AK) contributes to castrate resistance in prostate cancer (PCa) and that inhibiting AK with alisertib can resensitize PCa cells to androgen receptor (AR) inhibitor abiraterone...
November 2016: Oncologist
https://www.readbyqxmd.com/read/28177880/aurora-kinase-a-interacts-with-h-ras-and-potentiates-ras-mapk-signaling
#15
MaKendra Umstead, Jinglin Xiong, Qi Qi, Yuhong Du, Haian Fu
In cancer, upregulated Ras promotes cellular transformation and proliferation in part through activation of oncogenic Ras-MAPK signaling. While directly inhibiting Ras has proven challenging, new insights into Ras regulation through protein-protein interactions may offer unique opportunities for therapeutic intervention. Here we report the identification and validation of Aurora kinase A (Aurora A) as a novel Ras binding protein. We demonstrate that the kinase domain of Aurora A mediates the interaction with the N-terminal domain of H-Ras...
February 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28167680/aurora-a-twist1-axis-promotes-highly-aggressive-phenotypes-in-pancreatic-carcinoma
#16
Jing Wang, Kumar Nikhil, Keith Viccaro, Lei Chang, Max Jacobsen, George Sandusky, Kavita Shah
We uncovered a crucial role of Aurora kinase A (AURKA)-Twist1 axis in promoting epithelial-to-mesenchymal transition (EMT) and chemoresistance in pancreatic cancer. Twist1 is the first EMT-specific target of AURKA that was identified using an innovative screen. AURKA phosphorylates Twist1 at three sites, which results in its multifaceted regulation- AURKA inhibits its ubiquitylation, increases transcriptional activity, and favors homodimerization. Twist1 reciprocates and prevents AURKA degradation, thereby triggering a feedback loop...
February 6, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28166210/a-water-mediated-allosteric-network-governs-activation-of-aurora-kinase-a
#17
Soreen Cyphers, Emily F Ruff, Julie M Behr, John D Chodera, Nicholas M Levinson
The catalytic activity of many protein kinases is controlled by conformational changes of a conserved Asp-Phe-Gly (DFG) motif. We used an infrared probe to track the DFG motif of the mitotic kinase Aurora A (AurA) and found that allosteric activation by the spindle-associated protein Tpx2 involves an equilibrium shift toward the active DFG-in state. Förster resonance energy transfer experiments show that the activation loop undergoes a nanometer-scale movement that is tightly coupled to the DFG equilibrium...
April 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28147341/aurora-kinases-novel-therapy-targets-in-cancers
#18
REVIEW
Anqun Tang, Keyu Gao, Laili Chu, Rui Zhang, Jing Yang, Junnian Zheng
Aurora kinases, a family of serine/threonine kinases, consisting of Aurora A (AURKA), Aurora B (AURKB) and Aurora C (AURKC), are essential kinases for cell division via regulating mitosis especially the process of chromosomal segregation. Besides regulating mitosis, Aurora kinases have been implicated in regulating meiosis. The deletion of Aurora kinases could lead to failure of cell division and impair the embryonic development. Overexpression or gene amplification of Aurora kinases has been clarified in a number of cancers...
January 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28147331/aurora-a-kinase-inhibition-enhances-oncolytic-herpes-virotherapy-through-cytotoxic-synergy-and-innate-cellular-immune-modulation
#19
Mark A Currier, Les Sprague, Tilat A Rizvi, Brooke Nartker, Chun-Yu Chen, Pin-Yi Wang, Brian J Hutzen, Meghan R Franczek, Ami V Patel, Katherine E Chaney, Keri A Streby, Jeffrey A Ecsedy, Joe Conner, Nancy Ratner, Timothy P Cripe
Malignant peripheral nerve sheath tumor (MPNST) and neuroblastoma models respond to the investigational small molecule Aurora A kinase inhibitor, alisertib. We previously reported that MPNST and neuroblastomas are also susceptible to oncolytic herpes virus (oHSV) therapy. Herein, we show that combination of alisertib and HSV1716(HSV1716), a virus derived from HSV-1 and attenuated by deletion of RL1, exhibits significantly increased antitumor efficacy compared to either monotherapy. Alisertib and HSV1716 reduced tumor growth and increased survival in two xenograft models of MPNST and neuroblastoma...
January 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28108243/tpx2-as-a-prognostic-indicator-and-potential-therapeutic-target-in-clear-cell-renal-cell-carcinoma
#20
Zachary A Glaser, Harold D Love, Shunhua Guo, Lan Gellert, Sam S Chang, Stanley Duke Herrell, Daniel A Barocas, David F Penson, Michael S Cookson, Peter E Clark
OBJECTIVES: Our aims were to determine if targeting protein for Xklp2 (TPX2) is correlated with clear cell renal cell carcinoma (ccRCC) histology and oncologic outcomes using The Cancer Genome Atlas (TCGA) and an institutional tissue microarray (TMA). METHODS: Clinicopathological data obtained from the TCGA consisted of 415 samples diagnosed with ccRCC. A TMA was constructed from tumors of 207 patients who underwent radical nephrectomy for ccRCC. TPX2 expression by immunohistochemistry on TMA was assessed by a genitourinary pathologist...
January 17, 2017: Urologic Oncology
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