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https://www.readbyqxmd.com/read/29118074/golgi-stress-induced-transcriptional-changes-mediated-by-mapk-signaling-and-three-ets-transcription-factors-regulate-mcl1-splicing
#1
Jan Baumann, Tatiana I Ignashkova, Sridhar R Chirasani, Silvia Ramírez-Peinado, Hamed Alborzinia, Mathieu Gendarme, Kyra Kuhnigk, Valentin Kramer, Ralph K Lindemann, Jan H Reiling
The secretory pathway is a major determinant of cellular homoeostasis. While research into secretory stress signaling has so far mostly focused on the ER, emerging data suggests that the Golgi itself serves as an important signaling hub capable of initiating stress responses. To systematically identify novel Golgi stress mediators, we performed a transcriptomic analysis of cells exposed to three different pharmacological compounds known to elicit Golgi fragmentation: brefeldin A (BFA), golgicide A (GCA) and monensin (MON)...
November 8, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29072681/demethylzeylasteral-inhibits-cell-proliferation-and-induces-apoptosis-through-suppressing-mcl1-in-melanoma-cells
#2
Yuzu Zhao, Jiang He, Jun Li, Xingzhi Peng, Xianxing Wang, Zhen Dong, Erhu Zhao, Yaling Liu, Zonghui Wu, Hongjuan Cui
Demethylzeylasteral is one of the extracts of Tripterygium wilfordii Hook F, which plays important roles in multiple biological processes such as inflammation inhibition, as well as immunosuppression. However, anti-cancer function and the underlying mechanisms of demethylzeylasteral in melanoma cells remain unclear. In this study, we demonstrate that demethylzeylasteral has an anti-tumor property in melanoma cells. Demethylzeylasteral not only inhibits cell proliferation through cell cycle arrest at S phase, but also induces cell apoptosis in melanoma cells...
October 26, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29063678/molecular-profiling-and-combinatorial-activity-of-cct068127-a-potent-cdk2-and-cdk9-inhibitor
#3
Steven R Whittaker, Clare Barlow, Mathew P Martin, Caterina Mancusi, Steve Wagner, Annette Self, Elaine Barrie, Robert Te Poele, Swee Sharp, Nathan Brown, Stuart Wilson, Wayne Jackson, Peter M Fischer, Paul A Clarke, Michael I Walton, Edward McDonald, Julian Blagg, Martin Noble, Michelle D Garrett, Paul Workman
Deregulation of the cyclin-dependent kinases (CDKs) has been implicated in the pathogenesis of multiple cancer types. Consequently, CDKs have garnered intense interest as therapeutic targets for the treatment of cancer. We describe herein the molecular and cellular effects of CCT068127, a novel inhibitor of CDK2 and CDK9. Optimised from the purine template of seliciclib, CCT068127 exhibits greater potency and selectivity against purified CDK2 and CDK9 and superior antiproliferative activity against human colon cancer and melanoma cell lines...
October 24, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29024646/the-epstein-barr-virus-regulome-in-lymphoblastoid-cells
#4
Sizun Jiang, Hufeng Zhou, Jun Liang, Catherine Gerdt, Chong Wang, Liangru Ke, Stefanie C S Schmidt, Yohei Narita, Yijie Ma, Shuangqi Wang, Tyler Colson, Benjamin Gewurz, Guoliang Li, Elliott Kieff, Bo Zhao
Epstein-Barr virus (EBV) transforms B cells to continuously proliferating lymphoblastoid cell lines (LCLs), which represent an experimental model for EBV-associated cancers. EBV nuclear antigens (EBNAs) and LMP1 are EBV transcriptional regulators that are essential for LCL establishment, proliferation, and survival. Starting with the 3D genome organization map of LCL, we constructed a comprehensive EBV regulome encompassing 1,992 viral/cellular genes and enhancers. Approximately 30% of genes essential for LCL growth were linked to EBV enhancers...
October 11, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/29018077/efficacy-of-venetoclax-as-targeted-therapy-for-relapsed-refractory-t-11-14-multiple-myeloma
#5
Shaji Kumar, Jonathan L Kaufman, Cristina Gasparetto, Joseph Mikhael, Ravi Vij, Brigitte Pegourie, Lofti Benboubker, Thierry Facon, Martine Amiot, Philippe Moreau, Elizabeth A Punnoose, Stefanie Alzate, Martin Dunbar, Tu Xu, Suresh K Agarwal, Sari Heitner Enschede, Joel D Leverson, Jeremy A Ross, Paulo C Maciag, Maria Verdugo, Cyrille Touzeau
Venetoclax is a selective, orally bioavailable BCL-2 inhibitor that induces cell death in MM cells, particularly in those harboring t(11;14), which express high levels of BCL-2 relative to BCL-XL and MCL-1. In this phase I study, patients with relapsed/refractory MM received venetoclax monotherapy. After a 2-week lead-in with weekly dose escalation, daily venetoclax was given at 300, 600, 900, or 1200 mg in dose-escalation cohorts and 1200 mg in the safety expansion. Dexamethasone could be added upon progression during treatment...
October 10, 2017: Blood
https://www.readbyqxmd.com/read/28978427/myc-and-mcl1-cooperatively-promote-chemotherapy-resistant-breast-cancer-stem-cells-via-regulation-of-mitochondrial-oxidative-phosphorylation
#6
Kyung-Min Lee, Jennifer M Giltnane, Justin M Balko, Luis J Schwarz, Angel L Guerrero-Zotano, Katherine E Hutchinson, Mellissa J Nixon, Mónica V Estrada, Violeta Sánchez, Melinda E Sanders, Taekyu Lee, Henry Gómez, Ana Lluch, J Alejandro Pérez-Fidalgo, Melissa Magdalene Wolf, Gabriela Andrejeva, Jeffrey C Rathmell, Stephen W Fesik, Carlos L Arteaga
Most patients with advanced triple-negative breast cancer (TNBC) develop drug resistance. MYC and MCL1 are frequently co-amplified in drug-resistant TNBC after neoadjuvant chemotherapy. Herein, we demonstrate that MYC and MCL1 cooperate in the maintenance of chemotherapy-resistant cancer stem cells (CSCs) in TNBC. MYC and MCL1 increased mitochondrial oxidative phosphorylation (mtOXPHOS) and the generation of reactive oxygen species (ROS), processes involved in maintenance of CSCs. A mutant of MCL1 that cannot localize in mitochondria reduced mtOXPHOS, ROS levels, and drug-resistant CSCs without affecting the anti-apoptotic function of MCL1...
October 3, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28974650/inhibition-of-the-oncogenic-fusion-protein-ews-fli1-causes-g2-m-cell-cycle-arrest-and-enhanced-vincristine-sensitivity-in-ewing-s-sarcoma
#7
Stefan K Zöllner, Saravana P Selvanathan, Garrett T Graham, Ryan M T Commins, Sung Hyeok Hong, Eric Moseley, Sydney Parks, Jessica N Haladyna, Hayriye V Erkizan, Uta Dirksen, Michael D Hogarty, Aykut Üren, Jeffrey A Toretsky
Ewing's sarcoma (ES) is a rare and highly malignant cancer that grows in the bones or surrounding tissues mostly affecting adolescents and young adults. A chimeric fusion between the RNA binding protein EWS and the ETS family transcription factor FLI1 (EWS-FLI1), which is generated from a chromosomal translocation, is implicated in driving most ES cases by modulation of transcription and alternative splicing. The small-molecule YK-4-279 inhibits EWS-FLI1 function and induces apoptosis in ES cells. We aimed to identify both the underlying mechanism of the drug and potential combination therapies that might enhance its antitumor activity...
October 3, 2017: Science Signaling
https://www.readbyqxmd.com/read/28966941/increased-expression-of-the-tight-junction-protein-tjp1-zo-1-is-associated-with-upregulation-of-taz-tead-activity-and-an-adult-tissue-stem-cell-signature-in-carfilzomib-resistant-multiple-myeloma-cells-and-high-risk-multiple-myeloma-patients
#8
Irene Riz, Robert G Hawley
Tight junction protein 1 (TJP1) has recently been proposed as a biomarker to identify multiple myeloma (MM) patients most likely to respond to bortezomib- and carfilzomib-based proteasome inhibitor regimens. Herein we report increased expression of TJP1 during the adaptive response mediating carfilzomib resistance in the LP-1/Cfz MM cell line. Moreover, increased TJP1 expression delineated a subset of relapsed/refractory MM patients on bortezomib-based therapy sharing an LP-1/Cfz-like phenotype characterized by activation of interacting transcriptional effectors of the Hippo signaling cascade (TAZ and TEAD1) and an adult tissue stem cell signature...
July 2017: Oncoscience
https://www.readbyqxmd.com/read/28945224/rarf-confers-ra-resistance-by-sequestering-rar-to-the-nucleolus-and-regulating-mcl1-in-leukemia-cells
#9
H Youn, H-K Lee, H-R Sohn, U-H Park, E-J Kim, B Youn, S-J Um
Retinoic acid (RA) has broad clinical applications for the treatment of various cancers, particularly acute promyelocytic leukemia. However, RA-based therapy is limited by relapse in patients associated with RA resistance, the mechanism of which is poorly understood. Here, we suggest a new molecular mechanism of RA resistance by a repressor, named RA resistance factor (RaRF). RaRF suppressed transcriptional activity of the RA receptor (RAR) by directly interacting with and sequestering RAR to the nucleolus in response to RA...
September 25, 2017: Oncogene
https://www.readbyqxmd.com/read/28939105/protein-kinase-c-eta-regulates-mcl-1-level-via-erk1
#10
Deepanwita Pal, Alakananda Basu
Protein kinase C (PKC)-eta (PKCη) is a member of the novel category of PKC family. It is overexpressed in breast cancer and was shown to inhibit apoptosis and contribute to chemoresistance. Since the anti-apoptotic Bcl-2 family protein myeloid cell leukemia-1 (Mcl-1) plays an important role in breast cancer cell survival and chemoresistance, we investigated if PKCη regulates Mcl-1 level. Silencing of PKCη decreased Mcl-1 in several breast cancer cells, including MCF-7 and T47D cells. PKCη depletion had no effect on MCL1 mRNA but the decrease in Mcl-1 by PKCη knockdown was blocked by proteasomal inhibitors, such as MG132 and lactacystin...
December 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28931068/erk1-2-signalling-protects-against-apoptosis-following-endoplasmic-reticulum-stress-but-cannot-provide-long-term-protection-against-bax-bak-independent-cell-death
#11
Nicola J Darling, Kathryn Balmanno, Simon J Cook
Disruption of protein folding in the endoplasmic reticulum (ER) causes ER stress. Activation of the unfolded protein response (UPR) acts to restore protein homeostasis or, if ER stress is severe or persistent, drive apoptosis, which is thought to proceed through the cell intrinsic, mitochondrial pathway. Indeed, cells that lack the key executioner proteins BAX and BAK are protected from ER stress-induced apoptosis. Here we show that chronic ER stress causes the progressive inhibition of the extracellular signal-regulated kinase (ERK1/2) signalling pathway...
2017: PloS One
https://www.readbyqxmd.com/read/28915653/dual-targeting-of-mdm2-and-bcl2-as-a-therapeutic-strategy-in-neuroblastoma
#12
Alan Van Goethem, Nurten Yigit, Myrthala Moreno-Smith, Sanjeev A Vasudevan, Eveline Barbieri, Frank Speleman, Jason Shohet, Jo Vandesompele, Tom Van Maerken
Wild-type p53 tumor suppressor activity in neuroblastoma tumors is hampered by increased MDM2 activity, making selective MDM2 antagonists an attractive therapeutic strategy for this childhood malignancy. Since monotherapy in cancer is generally not providing long-lasting clinical responses, we here aimed to identify small molecule drugs that synergize with idasanutlin (RG7388). To this purpose we evaluated 15 targeted drugs in combination with idasanutlin in three p53 wild type neuroblastoma cell lines and identified the BCL2 inhibitor venetoclax (ABT-199) as a promising interaction partner...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28901451/genomic-profile-of-oral-squamous-cell-carcinomas-with-an-adjacent-leukoplakia-or-with-an-erythroleukoplakia-that-evolved-after-the-treatment-of-primary-tumor-a-report-of-two-cases
#13
Ilda P Ribeiro, Francisco Marques, Leonor Barroso, Joana Rodrigues, Francisco Caramelo, Joana B Melo, Isabel M Carreira
Oral leukoplakia and erythroleukoplakia are common oral potentially malignant disorders diagnosed in the oral cavity. The specific outcome of these lesions remains to be elucidated, as their malignant transformation rate exhibits great variation. The ability to predict which of those potentially malignant lesions are likely to progress to cancer would be vital to guide their future clinical management. The present study reported two patients with tongue squamous cell carcinoma: Case study 1 was diagnosed with a simultaneous leukoplakia and case study 2 developed an erythroleukoplakia following the primary tumor treatment...
November 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28883470/cytoglobin-promotes-cardiac-progenitor-cell-survival-against-oxidative-stress-via-the-upregulation-of-the-nf%C3%AE%C2%BAb-inos-signal-pathway-and-nitric-oxide-production
#14
Shuning Zhang, Xiuchun Li, Frances L Jourd'heuil, Shunlin Qu, Neil Devejian, Edward Bennett, David Jourd'heuil, Chuanxi Cai
Human cardiac stem/progenitor cells (hCPCs) may serve in regenerative medicine to repair the infarcted heart. However, this approach is severely limited by the poor survival of donor cells. Recent studies suggest that the mammalian globin cytoglobin (CYGB) regulates nitric oxide (NO) metabolism and cell death. In the present study, we found that CYGB is expressed in hCPCs. Through molecular approaches aimed at increasing or decreasing CYGB expression in hCPCs, we found that CYGB functions as a pro-survival factor in response to oxidative stress...
September 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28881590/upregulation-of-microrna-125b-by-g-csf-promotes-metastasis-in-colorectal-cancer
#15
Xinghua Zhang, Xiao Ma, Huaying An, Changqing Xu, Wenjo Cao, Wei Yuan, Jie Ma
Although there are reports of miR-125b being dysregulated in colorectal cancer (CRC) and associated with CRC progression, little is known about its intrinsic regulatory mechanisms. Here we detected the expression of miR-125b in CRC tissues, subsequently investigated the effect of miR-125b on the proliferation, apoptosis, cell cycle and metastasis on CRC cells. Our results showed that the expression of miR-125b was significantly decreased in CRC tissues comparing to adjacent tissues. However, with the stimulation of Granulocyte colony-stimulating factor (G-CSF), which was highly expressed in CRC tissues, the expression of miR-125b could be improved...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28874163/expression-of-factors-involved-in-apoptosis-and-cell-survival-is-correlated-with-enzymes-synthesizing-lysophosphatidic-acid-and-its-receptors-in-granulosa-cells-originating-from-different-types-of-bovine-ovarian-follicles
#16
Emilia Sinderewicz, Katarzyna Grycmacher, Dorota Boruszewska, Ilona Kowalczyk-Zięba, Joanna Staszkiewicz, Tomasz Ślężak, Izabela Woclawek-Potocka
BACKGROUND: Lysophosphatidic acid (LPA) regulates reproductive processes in the cow. Ovarian granulosa cells play a pivotal role in follicle growth and development. Nevertheless, the role of LPA in the local regulation of granulosa cell function in different follicle categories in the bovine ovary has not been investigated. METHODS: Ovarian follicles were divided into healthy, transitional and atretic categories. The expression levels of AX, PLA2, LPARs and factors involved in apoptosis and cell survival processes in granulosa cells in different types of follicles were measured by real-time PCR...
September 6, 2017: Reproductive Biology and Endocrinology: RB&E
https://www.readbyqxmd.com/read/28865993/genetic-neutrophil-deficiency-ameliorates-cerebral-ischemia-reperfusion-injury
#17
Ryan A Frieler, Yutein Chung, Carolyn G Ahlers, George Gheordunescu, Jianrui Song, Thomas M Vigil, Yatrik M Shah, Richard M Mortensen
Neutrophils respond rapidly to cerebral ischemia and are thought to contribute to inflammation-mediated injury during stroke. Using myeloid Mcl1 knockout mice as a model of genetic neutrophil deficiency, we investigated the contribution of neutrophils to stroke pathophysiology. Myeloid Mcl1 knockout mice were subjected to transient middle cerebral artery occlusion and infarct size was assessed by MRI after 24h reperfusion. Immune cell mobilization and infiltration was assessed by flow cytometry. We found that myeloid Mcl1 knockout mice had significantly reduced infarct size when compared to heterozygous and wild type control mice (MyMcl1(+/+): 78...
December 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28861715/the-neuroprotective-transcription-factor-atf5-is-decreased-and-sequestered-into-polyglutamine-inclusions-in-huntington-s-disease
#18
Ivó H Hernández, Jesús Torres-Peraza, María Santos-Galindo, Eloísa Ramos-Morón, M Rosario Fernández-Fernández, María J Pérez-Álvarez, Antonio Miranda-Vizuete, José J Lucas
Activating transcription factor-5 (ATF5) is a stress-response transcription factor induced upon different cell stressors like fasting, amino-acid limitation, cadmium or arsenite. ATF5 is also induced, and promotes transcription of anti-apoptotic target genes like MCL1, during the unfolded protein response (UPR) triggered by endoplasmic reticulum stress. In the brain, high ATF5 levels are found in gliomas and also in neural progenitor cells, which need to decrease their ATF5 levels for differentiation into mature neurons or glia...
August 31, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28855351/non-hodgkin-and-hodgkin-lymphomas-select-for-overexpression-of-bclw
#19
Clare M Adams, Ramkrishna Mitra, Jerald Z Gong, Christine M Eischen
Purpose: B-cell lymphomas must acquire resistance to apoptosis during their development. We recently discovered BCLW, an antiapoptotic BCL2 family member thought only to contribute to spermatogenesis, was overexpressed in diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma. To gain insight into the contribution of BCLW to B-cell lymphomas and its potential to confer resistance to BCL2 inhibitors, we investigated the expression of BCLW and the other antiapoptotic BCL2 family members in six different B-cell lymphomas...
November 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28797244/a-lowered-26s-proteasome-activity-correlates-with-mantle-lymphoma-cell-lines-resistance-to-genotoxic-stress
#20
Khaoula Ben Younes, Simon Body, Élodie Costé, Pierre-Julien Viailly, Hadjer Miloudi, Clémence Coudre, Fabrice Jardin, Fatma Ben Aissa-Fennira, Brigitte Sola
BACKGROUND: Mantle cell lymphoma (MCL) is a B-cell hemopathy characterized by the t(11;14) translocation and the aberrant overexpression of cyclin D1. This results in an unrestrained cell proliferation. Other genetic alterations are common in MCL cells such as SOX11 expression, mutations of ATM and/or TP53 genes, activation of the NF-κB signaling pathway and NOTCH receptors. These alterations lead to the deregulation of the apoptotic machinery and resistance to drugs. We observed that among a panel of MCL cell lines, REC1 cells were resistant towards genotoxic stress...
August 10, 2017: BMC Cancer
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