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https://www.readbyqxmd.com/read/28513465/the-role-of-srsf1-in-cancer
#1
Elżbieta Sokół, Joanna Bogusławska, Agnieszka Piekiełko-Witkowska
SRSF1 jest wielofunkcyjnym białkiem biorącym udział w procesach związanych z metabolizmem RNA. Następstwem zaburzeń ekspresji SRSF1, obserwowanych w wielu typach nowotworów, są nieprawidłowości w składaniu pre-mRNA, zmiany stabilności transkryptów i poziomu translacji onkogenów oraz genów supresorowych. Regulując różnicowe składanie transkryptów genów CCND1, RAC1, KLF6, BCL2L1, MCL1 oraz CASP9, SRSF1 indukuje zmiany w cyklu komórkowym, proliferacji i apoptozie. Czynnik SRSF1 wpływa także na angiogenezę nowotworową i przerzutowanie, m...
May 17, 2017: Postȩpy Higieny i Medycyny Doświadczalnej
https://www.readbyqxmd.com/read/28504646/the-rna-binding-protein-tristetraprolin-schedules-apoptosis-of-pathogen-engaged-neutrophils-during-bacterial-infection
#2
Florian Ebner, Vitaly Sedlyarov, Saren Tasciyan, Masa Ivin, Franz Kratochvill, Nina Gratz, Lukas Kenner, Andreas Villunger, Michael Sixt, Pavel Kovarik
Protective responses against pathogens require a rapid mobilization of resting neutrophils and the timely removal of activated ones. Neutrophils are exceptionally short-lived leukocytes, yet it remains unclear whether the lifespan of pathogen-engaged neutrophils is regulated differently from that in the circulating steady-state pool. Here, we have found that under homeostatic conditions, the mRNA-destabilizing protein tristetraprolin (TTP) regulates apoptosis and the numbers of activated infiltrating murine neutrophils but not neutrophil cellularity...
May 15, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28499919/long-non-coding-rna-ac023115-3-suppresses-chemoresistance-of-glioblastoma-by-reducing-autophagy
#3
Binbin Ma, Zhongbo Yuan, Li Zhang, Peng Lv, Ting Yang, Jinxia Gao, Ning Pan, Qiong Wu, Jiacheng Lou, Chuanchun Han, Bo Zhang
Malignant glioma is an aggressive brain cancer that responds poorly to chemotherapy. However, the molecular mechanism underlying the development of chemoresistance in glioma is not well-understood. In this study, we show that long non-coding RNA AC023115.3 is induced by cisplatin in human glioblastoma cells and that elevated AC023115.3 promotes cisplatin-induced apoptosis by inhibiting autophagy. Further mechanistic studies revealed that AC023115.3 acts as a competing endogenous RNA for miR-26a and attenuates the inhibitory effect of miR-26a on GSK3β, a proline-directed serine-threonine kinase that promotes the degradation of Mcl1, leading to an increase in GSK3β and a decrease in autophagy...
May 9, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28472749/neutral-pegylated-liposomal-formulation-for-efficient-folate-mediated-delivery-of-mcl1-sirna-to-activated-macrophages
#4
Eugénia Nogueira, Jaime Freitas, Ana Loureiro, Patrícia Nogueira, Andreia C Gomes, Ana Preto, Alexandre M Carmo, Alexandra Moreira, Artur Cavaco-Paulo
Cationic liposomes are efficient vectors for systemic delivery of therapeutic small interfering RNA (siRNA), taking advantage of RNA interference (RNAi), a naturally occurring gene-silencing mechanism in mammalian cells. However, toxicity at high concentrations, short circulating half-lives and lack of specificity restrict their successful application in a wider scale. The purpose of this study was to evaluate the efficiency of neutral liposomes containing polyethylene glycol (PEG) to encapsulate siRNA in their aqueous core...
April 13, 2017: Colloids and Surfaces. B, Biointerfaces
https://www.readbyqxmd.com/read/28465444/histone-deacetylase-inhibitor-enhances-the-efficacy-of-mek-inhibitor-through-noxa-mediated-mcl1-degradation-in-triple-negative-and-inflammatory-breast-cancer
#5
Angie M Torres-Adorno, Jangsoon Lee, Takahiro Kogawa, Peter Ordentlich, Debu Tripathy, Bora Lim, Naoto T Ueno
Purpose: Inflammatory breast cancer (IBC), diagnosed clinically, and triple-negative breast cancer (TNBC), diagnosed by molecular receptor status, are the two most aggressive forms of breast cancer, and both lack effective targeted therapies. We previously demonstrated involvement of histone deacetylase (HDAC) inhibitor entinostat in regulating apoptosis in IBC and TNBC cells; here, we aimed to identify novel combination therapy candidates. <p>Experimental Design: Potential therapeutic targets were identified by mRNA expression profiling of TNBC and IBC cells treated with entinostat...
May 2, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28451058/specific-phospholipid-scramblases-are-involved-in-exposure-of-phosphatidylserine-an-eat-me-signal-for-phagocytes-on-degenerating-axons
#6
Shuji Wakatsuki, Toshiyuki Araki
Axonal degeneration is a key pathological feature of several neurological disorders. Emerging evidence has suggested a pathological connection between axonal degeneration and autophagy, a lysosomal degradation pathway. We recently reported that GSK3B-mediated phosphorylation of MCL1 regulates axonal autophagy to promote axonal degeneration. GSK3B-MCL1 pathway affects ATP production locally in degenerating axons and the exposure of phosphatidylserine (PS), an "eat-me" signal for phagocytes, on degenerating axons, resulting in the failed engulfment of axonal debris in vivo...
2017: Communicative & Integrative Biology
https://www.readbyqxmd.com/read/28449207/targeting-anti-apoptotic-bcl2-family-proteins-in-haematological-malignancies-from-pathogenesis-to-treatment
#7
REVIEW
Meike Vogler, Harriet S Walter, Martin J S Dyer
The B-cell lymphoma 2 (BCL2) family of proteins comprise key regulators of apoptosis and are implicated in the pathogenesis of many malignancies, including lymphomas and leukaemias. Targeting of BCL2 proteins can be directly toxic to tumour cells or render them more sensitive to chemotherapy. Inhibition of the anti-apoptotic functions of BCL2 proteins using structure-based design to produce specific inhibitors of protein-protein interactions has been achieved for BCL2, MCL1 and BCL-XL (also termed BCL2L1), providing an armamentarium of new targeted therapies called BH3-mimetics...
April 27, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28445949/lmp1-slamf1high-cells-are-associated-with-drug-resistance-in-epstein-barr-virus-positive-farage-cells
#8
Heejei Yoon, Young Hyeh Ko
How Epstein-Barr virus (EBV) affects the clinical outcome of EBV-positive diffuse large B-cell lymphoma (DLBCL) remains largely unknown. The viral oncogene LMP1 is at the crux of tumorigenesis and cell survival. Therefore, we examined the association between LMP1high cells drug resistance. We first assessed SLAMF1 as a surrogate marker for LMP1high cells. LMP1 and its target gene CCL22 were highly expressed in SLAMF1high Farage cells. These cells survived longer following treatment with a combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28431404/upregulation-of-microrna-125b-by-g-csf-promotes-metastasis-in-colorectal-cancer
#9
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...
April 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28420096/a-network-based-pharmacology-study-of-the-herb-induced-liver-injury-potential-of-traditional-hepatoprotective-chinese-herbal-medicines
#10
Ming Hong, Sha Li, Hor Yue Tan, Fan Cheung, Ning Wang, Jihan Huang, Yibin Feng
Herbal medicines are widely used for treating liver diseases and generally regarded as safe due to their extensive use in Traditional Chinese Medicine practice for thousands of years. However, in recent years, there have been increased concerns regarding the long-term risk of Herb-Induced Liver Injury (HILI) in patients with liver dysfunction. Herein, two representative Chinese herbal medicines: one-Xiao-Chai-Hu-Tang (XCHT)-a composite formula, and the other-Radix Polygoni Multiflori (Heshouwu)-a single herb, were analyzed by network pharmacology study...
April 14, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28415610/the-tubulin-inhibitor-mg-2477-induces-autophagy-regulated-cell-death-ros-accumulation-and-activation-of-foxo3-in-neuroblastoma
#11
Judith Hagenbuchner, Lorena Lungkofler, Ursula Kiechl-Kohlendorfer, Giampietro Viola, Maria Grazia Ferlin, Michael J Ausserlechner, Petra Obexer
Neuroblastoma is the most frequent extra-cranial solid tumor in children with still high mortality in stage M. Here we studied the tubulin-inhibitor MG-2477 as a possible therapeutic agent for neuroblastoma therapy and uncovered that MG-2477 induces death in neuroblastoma cells independent of PKB-activation status and stage. MG-2477 triggers within 30 minutes extensive autophagosome-formation that finally leads to cell death associated with mitotic catastrophe. Autophagy is critical for MG-2477-induced death and is regulated by the BH3-only protein PMAIP1/NOXA which sequesters the anti-apoptotic BCL2-protein BCLXL and thereby displaces and activates the autophagy-regulator BECN1/beclin1...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415602/errf-sensitizes-erbb2-positive-breast-cancer-cells-to-lapatinib-treatment-likely-by-attenuating-mcl1-and-erbb2-expression
#12
Leilei Qi, Baotong Zhang, Shiying Zhang, Xinpei Ci, Qiao Wu, Gui Ma, Ang Luo, Liya Fu, Jamie L King, Rita Nahta, Jin-Tang Dong
Previously we found that the estrogen receptor (ER) related factor ERRF regulates cell proliferation and tumor growth, and its expression is positively associated with ER status and better survival but inversely associated with ERBB2 (also named HER2) status in breast cancer. Here we report that ERRF also plays an important role in the response of ERBB2-positive breast cancer cells to lapatinib, a dual tyrosine kinase inhibitor that interrupts the ERBB2 and EGFR pathway. In ERBB2-positive breast cancer cell lines, lower levels of ERRF expression correlated with lapatinib resistance, restoration of ERRF expression in lapatinib-resistant cell lines JIMT-1 and MDA-MB-453 enhanced their lapatinib responses, and knockdown of ERRF in lapatinib sensitive cell lines BT-474 and SK-BR-3 caused lapatinib resistance...
March 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28368400/interferon-%C3%AE-is-a-stat1-dependent-direct-inducer-of-bcl6-expression-in-imatinib-treated-chronic-myeloid-leukemia-cells
#13
H S Madapura, N Nagy, D Ujvari, T Kallas, M C L Kröhnke, S Amu, M Björkholm, L Stenke, P K Mandal, J S McMurray, M Keszei, L S Westerberg, H Cheng, F Xue, G Klein, E Klein, D Salamon
B-cell CLL/lymphoma 6 (BCL6) exerts oncogenic effects in several human hematopoietic malignancies including chronic myeloid leukemia (CML), where BCL6 expression was shown to be essential for CML stem cell survival and self-renewal during imatinib mesylate (IM) treatment. As several lines of evidence suggest that interferon γ (IFNγ) production in CML patients might have a central role in the response to tyrosine kinase inhibitor (TKI) therapy, we analyzed if IFNγ modulates BCL6 expression in CML cells. Although separate IFNγ or IM treatment only slightly upregulated BCL6 expression, combined treatment induced remarkable BCL6 upregulation in CML lines and primary human CD34+ CML stem cells...
April 3, 2017: Oncogene
https://www.readbyqxmd.com/read/28319085/synergistic-drug-combinations-for-cancer-identified-in-a-crispr-screen-for-pairwise-genetic-interactions
#14
Kyuho Han, Edwin E Jeng, Gaelen T Hess, David W Morgens, Amy Li, Michael C Bassik
Identification of effective combination therapies is critical to address the emergence of drug-resistant cancers, but direct screening of all possible drug combinations is infeasible. Here we introduce a CRISPR-based double knockout (CDKO) system that improves the efficiency of combinatorial genetic screening using an effective strategy for cloning and sequencing paired single guide RNA (sgRNA) libraries and a robust statistical scoring method for calculating genetic interactions (GIs) from CRISPR-deleted gene pairs...
May 2017: Nature Biotechnology
https://www.readbyqxmd.com/read/28295185/dual-targeting-of-mcl1-and-noxa-as-effective-strategy-for-treatment-of-mantle-cell-lymphoma
#15
Elisabeth Höring, Arnau Montraveta, Simon Heine, Markus Kleih, Lea Schaaf, Matthias C Vöhringer, Anna Esteve-Arenys, Gael Roué, Dolors Colomer, Elias Campo, German Ott, Walter E Aulitzky, Heiko van der Kuip
Imbalances in the composition of BCL2 family proteins contribute to tumourigenesis and therapy resistance of mantle cell lymphoma (MCL), making these proteins attractive therapy targets. We studied the efficiency of dual targeting the NOXA/MCL1 axis by combining fatty acid synthase inhibitors (NOXA stabilization) with the CDK inhibitor Dinaciclib (MCL1 reduction). This combination synergistically induced apoptosis in cell lines and primary MCL cells and led to almost complete inhibition of tumour progression in a mouse model...
March 14, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28274596/aberrant-expression-of-deubiquitylating-enzyme-usp9x-predicts-poor-prognosis-in-gastric-cancer
#16
Xiang Fu, Wei Xie, Xiaoxue Song, Kun Wu, Linkang Xiao, Yongqiang Liu, Lei Zhang
BACKGROUND: Ubiquitin-specific peptidase 9, X-linked (USP9X), a member of deubiquitylating enzymes family, has recently been reported to be associated with a variety of cancer progression. While it functions as either oncogene or tumor suppressor in a context-dependent manner, the expression and role of USP9X in gastric cancer is largely unknown. METHODS: Sixty-eight cases of patients with gastric cancer were enrolled in this study. The expression of USP9X and MCL1 were detected by immunohistochemistry...
March 5, 2017: Clinics and Research in Hepatology and Gastroenterology
https://www.readbyqxmd.com/read/28215535/ambra1-a-novel-bh3-like-protein-new-insights-into-the-ambra1-bcl2-family-proteins-relationship
#17
A Di Rita, F Strappazzon
Cellular homeostasis swings like a pendulum backward and forward between life and death. Two of the main processes, which regulate this equilibrium, are autophagy and apoptosis. While autophagy is a highly conserved self-digestion mechanism that mediates degradation of damaged or surplus components, apoptosis is a programmed cell suicide in which typical death signals induce the elimination of undesired cells. Both these processes are highly regulated by complex molecular machineries, including some common proteins whose "dual role" favors one process or the other...
2017: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/28209992/from-basic-apoptosis-discoveries-to-advanced-selective-bcl-2-family-inhibitors
#18
REVIEW
Avi Ashkenazi, Wayne J Fairbrother, Joel D Leverson, Andrew J Souers
Members of the B cell lymphoma 2 (BCL-2) gene family have a central role in regulating programmed cell death by controlling pro-apoptotic and anti-apoptotic intracellular signals. In cancer, apoptosis evasion through dysregulation of specific BCL-2 family genes is a recurring event; accordingly, selective inhibition of specific anti-apoptotic BCL-2 family proteins represents an exciting therapeutic opportunity. A combination of nuclear magnetic resonance (NMR)-based screening and structure-based drug design has yielded the first bona fide BCL-2 homology 3 (BH3) mimetics, including the BCL-2 and BCL-XL dual antagonist navitoclax, which is the first BCL-2 family inhibitor to show efficacy in patients with cancer...
April 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/28209615/targeted-degradation-of-bet-proteins-in-triple-negative-breast-cancer
#19
Longchuan Bai, Bing Zhou, Chao-Yie Yang, Jiao Ji, Donna McEachern, Sally Przybranowski, Hui Jiang, Jiantao Hu, Fuming Xu, Yujun Zhao, Liu Liu, Ester Fernandez-Salas, Jing Xu, Yali Dou, Bo Wen, Duxin Sun, Jennifer Meagher, Jeanne Stuckey, Daniel F Hayes, Shunqiang Li, Matthew J Ellis, Shaomeng Wang
Triple-negative breast cancers (TNBC) remain clinically challenging with a lack of options for targeted therapy. In this study, we report the development of a second-generation BET protein degrader, BETd-246, which exhibits superior selectivity, potency, and antitumor activity. In human TNBC cells, BETd-246 induced degradation of BET proteins at low nanomolar concentrations within 1 hour of exposure, resulting in robust growth inhibition and apoptosis. BETd-246 was more potent and effective in TNBC cells than its parental BET inhibitor compound BETi-211...
May 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/28187444/idelalisib-and-bendamustine-combination-is-synergistic-and-increases-dna-damage-response-in-chronic-lymphocytic-leukemia-cells
#20
Prexy Modi, Kumudha Balakrishnan, Qingshan Yang, William G Wierda, Michael J Keating, Varsha Gandhi
Idelalisib is a targeted agent that potently inhibits PI3Kδ which is exclusively expressed in hematological cells. Bendamustine is a well-tolerated cytotoxic alkylating agent which has been extensively used for treatment of chronic lymphocytic leukemia (CLL). Both these agents are FDA-approved for CLL. To increase the potency of idelalisib and bendamustine, we tested their combination in primary CLL lymphocytes. While each compound alone produced a moderate response, combination at several concentrations resulted in synergistic cytotoxicity...
March 7, 2017: Oncotarget
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