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https://www.readbyqxmd.com/read/28918350/expression-and-functional-characterization-of-the-bnip3-protein-in-renal-cell-carcinomas
#1
Stephan Macher-Goeppinger, Martina Keith, Gencay Hatiboglu, Markus Hohenfellner, Peter Schirmacher, Wilfried Roth, Katrin E Tagscherer
BNIP3 (Bcl-2/adenovirus E1B 19-kDa interacting protein 3) is a BH3-only protein that regulates apoptosis and autophagy. BNIP3 plays also an important role in hypoxia-induced cell response and is regulated by HIF1. Here, we studied a possible association of BNIP3 expression and the prognosis of patients with renal cell carcinomas (RCCs) and examined the functional relevance of BNIP3 in the regulation of cell survival and apoptosis of renal carcinoma cells. BNIP3 expression was determined by immunohistochemistry in RCC tumor tissue samples of 569 patients using a tissue microarray...
September 14, 2017: Translational Oncology
https://www.readbyqxmd.com/read/28903561/enhanced-sampling-of-intrinsic-structural-heterogeneity-of-the-bh3-only-protein-binding-interface-of-bcl-xl
#2
Xiaorong Liu, Zhiguang Jia, Jianhan Chen
Anti-apoptotic Bcl-xL plays central roles in regulating programed cell death. Partial unfolding of Bcl-xL has been observed at the interface upon specific binding to the pro-apoptotic BH3-only protein PUMA, which in turn disrupts the interaction of Bcl-xL with tumor suppressor p53 and promotes apoptosis. Previous analysis of existing Bcl-xL structures and atomistic molecular dynamics (MD) simulations have suggested that substantial intrinsic structure heterogeneity exists at the BH3-only protein binding interface of Bcl-xL to facilitate its conformational transitions upon binding...
September 13, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28902352/gper-promotes-tamoxifen-resistance-in-er-breast-cancer-cells-by-reduced-bim-proteins-through-mapk-erk-trim2-signaling-axis
#3
Heng Yin, Qing Zhu, Manran Liu, Gang Tu, Qing Li, Jie Yuan, Siyang Wen, Guanglun Yang
Tamoxifen resistance is a major clinical challenge in breast cancer treatment. Our previous studies find that GPER and its down-stream signaling play a pivotal role in the development of tamoxifen (TAM) resistance. cDNA array analysis indicated a set of genes associated with cell apoptosis are aberrant in GPER activated and TAM-resistant MCF-7R cells compared with TAM-sensitive MCF-7 cells. Among these genes, Bim (also named BCL2-L11), a member of the BH3-only pro-apoptotic protein family is significantly decreased, and TRIM RING finger protein TRIM2 (a ubiquitin ligase) is highly expressed in MCF-7R...
September 5, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28902204/rational-design-and-structure-activity-relationship-studies-of-quercetin-amino-acid-hybrids-targeting-the-anti-apoptotic-protein-bcl-xl
#4
Tahsin F Kellici, Maria V Chatziathanasiadou, Min-Sung Lee, Nisar Sayyad, Elena G Geromichalou, Eirinaios I Vrettos, Antonis D Tsiailanis, Seung-Wook Chi, George D Geromichalos, Thomas Mavromoustakos, Andreas G Tzakos
Anti-apoptotic proteins, like the Bcl-2 family proteins, present an important therapeutic cancer drug target. Their activity is orchestrated through neutralization upon interaction of pro-apoptotic protein counterparts that leads to immortality of cancer cells. Therefore, generating compounds targeting these proteins is of immense therapeutic importance. Herein, Induced Fit Docking (IFD) and Molecular Dynamics (MD) simulations were performed to rationally design quercetin analogues that bind in the BH3 site of the Bcl-xL protein...
September 13, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28901269/recent-advances-in-cancer-drug-development-targeting-induced-myeloid-cell-leukemia-1-mcl-1-differentiation-protein
#5
Mohammad Abid, Yogesh A Sonawane, Jacob I Contreras, Sandeep Rana, Amarnath Natarajan
BACKGROUND: Anti-apoptotic members of the Bcl-2 family of proteins are upregulated in a majority of cancers and are potential therapeutic targets. Fragment-based design led to the development of clinical candidates that target Bcl-xL/Bcl-2. Although these Bcl-xL/Bcl-2 inhibitors showed promise in pre-clinical studies, resistance was observed to several Bcl-xL inhibitors, when used alone. This has been attributed to the over-expression of Mcl-1, another member of the Bcl-2 family of proteins...
September 11, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28888620/the-caspase-8-bid-cytochrome-c-axis-links-signals-from-death-receptors-to-mitochondrial-reactive-oxygen-species-production
#6
Wan-Sung Kim, Kwang-Soon Lee, Ji-Hee Kim, Chun-Ki Kim, Gwangsoo Lee, Jongseon Choe, Moo-Ho Won, Tae-Hyoung Kim, Dooil Jeoung, Hansoo Lee, Ji-Yoon Kim, Mi Ae Jeong, Kwon-Soo Ha, Young-Guen Kwon, Young-Myeong Kim
Ligation of the death receptors for TNF-α, FasL, and TRAIL triggers two common pathways, caspase-dependent intrinsic apoptosis and intracellular reactive oxygen species (ROS) generation. The apoptotic pathway is well characterized; however, a signaling linker between the death receptor and ROS production has not been clearly elucidated. Here, we found that death receptor-induced ROS generation was strongly inhibited by mitochondrial complex I and II inhibitors, but not by inhibitors of NADPH oxidase, lipoxygenase, cyclooxygenase or xanthine oxidase, indicating that ROS are mostly generated by the impairment of the mitochondrial respiratory chain...
September 6, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28883393/fas-cell-surface-death-receptor-controls-hepatic-lipid-metabolism-by-regulating-mitochondrial-function
#7
Flurin Item, Stephan Wueest, Vera Lemos, Sokrates Stein, Fabrizio C Lucchini, Rémy Denzler, Muriel C Fisser, Tenagne D Challa, Eija Pirinen, Youngsoo Kim, Silvio Hemmi, Erich Gulbins, Atan Gross, Lorraine A O'Reilly, Markus Stoffel, Johan Auwerx, Daniel Konrad
Nonalcoholic fatty liver disease is one of the most prevalent metabolic disorders and it tightly associates with obesity, type 2 diabetes, and cardiovascular disease. Reduced mitochondrial lipid oxidation contributes to hepatic fatty acid accumulation. Here, we show that the Fas cell surface death receptor (Fas/CD95/Apo-1) regulates hepatic mitochondrial metabolism. Hepatic Fas overexpression in chow-fed mice compromises fatty acid oxidation, mitochondrial respiration, and the abundance of mitochondrial respiratory complexes promoting hepatic lipid accumulation and insulin resistance...
September 7, 2017: Nature Communications
https://www.readbyqxmd.com/read/28882984/transient-apoptosis-inhibition-in-donor-stem-cells-improves-hematopoietic-stem-cell-transplantation
#8
Matthias Kollek, Gesina Voigt, Christian Molnar, Fabronia Murad, Daniela Bertele, Christopher Felix Krombholz, Sheila Bohler, Verena Labi, Stefan Schiller, Mirjam Kunze, Stephan Geley, Charlotte M Niemeyer, Ana Garcia-Saez, Miriam Erlacher
During hematopoietic stem cell transplantation, a substantial number of donor cells are lost because of apoptotic cell death. Transplantation-associated apoptosis is mediated mainly by the proapoptotic BCL-2 family proteins BIM and BMF, and their proapoptotic function is conserved between mouse and human stem and progenitor cells. Permanent inhibition of apoptosis in donor cells caused by the loss of these BH3-only proteins improves transplantation outcome, but recipients might be exposed to increased risk of lymphomagenesis or autoimmunity...
September 7, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28878321/a-natural-chalcone-induces-apoptosis-in-lung-cancer-cells-3d-qsar-docking-and-an-in-vivo-vitro-assay
#9
Gang Chen, Di Zhou, Xue-Zheng Li, Zhe Jiang, Chengyu Tan, Xiu-Yan Wei, Junhong Ling, Jing Jing, Fen Liu, Ning Li
This study was to study the antitumor effect of lonchocarpin (34) from traditional herbal medicine Pongamia pinnata (L.) Pierre and to reveal the underlying mechanism. The cytotoxic activities of lonchocarpin were evaluated in 10 lung cancer cell lines and it exhibited 97.5% activity at a dose of 100 μM in the H292 cell line. A field-based quantitative structure-activity relationship (3D-QSAR) study of 37 flavonoids from P. pinnata was also performed, and the results obtained showed that the hydrophobic interaction could be the crucial factor for the antitumor activity of lonchocarpin...
September 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28877995/a-neuroprotective-agent-that-inactivates-prodegenerative-trka-and-preserves-mitochondria
#10
Konstantin Feinberg, Adelaida Kolaj, Chen Wu, Natalie Grinshtein, Jonathan R Krieger, Michael F Moran, Lee L Rubin, Freda D Miller, David R Kaplan
Axon degeneration is an early event and pathological in neurodegenerative conditions and nerve injuries. To discover agents that suppress neuronal death and axonal degeneration, we performed drug screens on primary rodent neurons and identified the pan-kinase inhibitor foretinib, which potently rescued sympathetic, sensory, and motor wt and SOD1 mutant neurons from trophic factor withdrawal-induced degeneration. By using primary sympathetic neurons grown in mass cultures and Campenot chambers, we show that foretinib protected neurons by suppressing both known degenerative pathways and a new pathway involving unliganded TrkA and transcriptional regulation of the proapoptotic BH3 family members BimEL, Harakiri,and Puma, culminating in preservation of mitochondria in the degenerative setting...
September 6, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28869600/foxo3-mediated-chemo-protection-in-high-stage-neuroblastoma-depends-on-wild-type-tp53-and-sesn3
#11
M Rupp, J Hagenbuchner, B Rass, H Fiegl, U Kiechl-Kohlendorfer, P Obexer, M J Ausserlechner
Forkhead box O class transcription factors are homeostasis regulators that control cell death, longevity and therapy-resistance. In neuroblastoma (NB), nuclear FOXO3 correlates with stage M disease and poor prognosis. To analyze whether FOXO3 contributes to drug-resistance in this childhood cancer, we investigated how different high-stage-derived NB cells respond to the activation of an ectopic FOXO3 allele. We found endogenous FOXO3 mostly localized to the nucleus-upon activation of an ectopic, 4OHT-activated FOXO3(A3)ER fusion protein two of the cell lines underwent apoptosis, whereas in the others FOXO3-activation even increased survival during drug-treatment...
September 4, 2017: Oncogene
https://www.readbyqxmd.com/read/28868037/bh3-mimetics-for-the-treatment-of-prostate-cancer
#12
Philipp Wolf
Despite improved diagnostic and therapeutic intervention, advanced prostate cancer (PC) remains incurable. The acquired resistance of PC cells to current treatment protocols has been traced to apoptosis resistance based on the upregulation of anti-apoptotic proteins of the Bcl-2 family. The use of BH3 mimetics, mimicking pro-apoptotic activator or sensitizer proteins of the intrinsic apoptotic pathway, is therefore a promising treatment strategy. The present review gives an overview of preclinical and clinical studies with pan- and specific BH3 mimetics as sensitizers for cell death and gives an outlook how they could be effectively used for the therapy of advanced PC in future...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28853467/h-d-scrambling-in-a-chromium-catalyzed-dehydrocoupling-reaction-of-a-borane-dimethylamine-adduct
#13
Yasuro Kawano, Mamoru Shimoi
H/D scrambling took place in a chromium-catalyzed dehydrocoupling reaction of a deuterium-labeled borane-dimethylamine adduct. In the hydrogen elimination of BH3·NDMe2 (1a-dN), H2, HD and D2 were generated in 65 : 30 : 5 ratio, and 62% of deuterium atoms were incorporated into the major product, the dimethylaminoborane dimer. Proton and deuteron nuclei were thus concentrated into the evolved dihydrogen and aminoborane dimer, respectively. The mechanism of H/D scrambling is understood based on the reaction pathway of the dehydrocoupling of 1a, which was previously proposed based on DFT calculations...
September 12, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/28851813/the-influential-role-of-bcl2-family-members-in-synovial-sarcomagenesis
#14
Jared J Barrott, Ju-Fen Zhu, Kyllie Smith-Fry, Asia M Susko, Dakota Nollner, Lance Burrell, Amir Pozner, Mario R Capecchi, Jeffrey T Yap, Lisa A Cannon-Albright, Xingming Deng, Kevin B Jones
Synovial sarcomas are deadly soft-tissue malignancies associated with t(X;18) balanced chromosomal translocations. Expression of the apoptotic regulator BCL2 is prominent in synovial sarcomas and has prompted the hypothesis that synovial sarcomagenesis may depend on it. Herein, it is demonstrated that Bcl2 overexpression enhances synovial sarcomagenesis in an animal model. Further, we determined increased familial clustering of human synovial sarcoma patients with victims of other BCL2-associated malignancies in the Utah Population Database...
August 29, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28844952/targeting-cholangiocarcinoma
#15
REVIEW
Joachim C Mertens, Sumera Rizvi, Gregory J Gores
Cholangiocarcinoma (CCA) represents a diverse group of epithelial cancers associated with the biliary tract, and can best be stratified anatomically into intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) subsets. Molecular profiling has identified genetic aberrations associated with these anatomic subsets. For example, IDH catalytic site mutations and constitutively active FGFR2 fusion genes are predominantly identified in iCCA, whereas KRAS mutations and PRKACB fusions genes are identified in pCCA and dCCA...
August 24, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28843007/bcl-2-protects-tk6-cells-against-hydroquinone-induced-apoptosis-through-parp-1-cytoplasm-translocation-and-stabilizing-mitochondrial-membrane-potential
#16
Yuting Chen, Shaoyun Chen, Hairong Liang, Hui Yang, Linhua Liu, Kairu Zhou, Longmei Xu, Jiaxian Liu, Lin Yun, Bei Lai, Li Song, Hao Luo, Jianming Peng, Zhidong Liu, Yongmei Xiao, Wen Chen, Huanwen Tang
B cell leukemia/lymphoma-2 (Bcl-2) suppresses apoptosis by binding the BH3 domain of proapoptotic factors and thereby regulating mitochondrial membrane potential (MMP). This study aimed to investigate the role of Bcl-2 in controlling the mitochondrial pathway of apoptosis during hydroquinone (HQ)-induced TK6 cytotoxicity. In this study, HQ, one metabolite of benzene, decreased the MMP in a concentration-dependent manner and induced the generation of reactive oxygen species (ROS), the activation of the DNA damage marker γ-H2AX, and production of the DNA damage-responsive enzyme poly(ADP-ribose)polymerase-1 (PARP-1)...
August 26, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28838268/rational-combination-strategies-to-enhance-venetoclax-activity-and-overcome-resistance-in-hematologic-malignancies
#17
Steven Grant
Venetoclax (ABT-199) is a Bcl-2-specific BH3-mimetic that has shown significant promise in certain subtypes of CLL as well as in several other hematologic malignancies. As in the case of essentially all targeted agents, intrinsic or acquired resistance to this agent generally occurs, prompting the search for new strategies capable of circumventing this problem. A logical approach to this challenge involves rational combination strategies designed to disable preexisting or induced compensatory survival pathways...
August 24, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28820241/interactions-of-verkade-s-superbase-with-strong-lewis-acids-from-labile-mono-and-binuclear-lewis-acid-base-complexes-to-phosphenium-cations
#18
Suresh Mummadi, Dustin Kenefake, Rony Diaz, Daniel K Unruh, Clemens Krempner
A series of mono- and binuclear Lewis acid-base complexes of the formulas N[CH2CH2N(Pr(i))]3P→LA [LA = BH3 (8), Ga(C6F5)3 (10), GaCl3 (11)], LA←N[CH2CH2N(Pr(i))]3P [LA = Al(C6F5)3 (6a), AlMe3 (6b), AlEt3 (6c), AlBu(i)3 (6d), BF3 (13)], and LA←N[CH2CH2N(Pr(i))]3P→LA [Lewis acid (LA) = Al(C6F5)3 (7a), AlMe3 (7b), AlEt3 (7c), AlBu(i)3 (7d), AlCl3 (7e), BH3 (9)] were generated from reactions of Verkade's base, N[CH2CH2N(Pr(i))]3P (1), with various boron-, aluminum-, and gallium-containing Lewis acids, and characterized by multinuclear NMR spectroscopy...
August 18, 2017: Inorganic Chemistry
https://www.readbyqxmd.com/read/28807790/the-functional-domains-for-bax%C3%A2-2-aggregate-mediated-caspase-8-dependent-cell-death
#19
Adriana Mañas, Sheng Wang, Adam Nelson, Jiajun Li, Yu Zhao, Huaiyuan Zhang, Aislinn Davis, Bingqing Xie, Natalia Maltsev, Jialing Xiang
Bax∆2 is a functional pro-apoptotic Bax isoform having alterations in its N-terminus, but sharing the rest of its sequence with Baxα. Bax∆2 is unable to target mitochondria due to the loss of helix α1. Instead, it forms cytosolic aggregates and activates caspase 8. However, the functional domain(s) responsible for BaxΔ2 behavior have remained elusive. Here we show that disruption of helix α1 makes Baxα mimic the behavior of Bax∆2. However, the other alterations in the Bax∆2 N-terminus have no significant impact on aggregation or cell death...
August 12, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28806067/immunosensor-employing-stable-solid-1-amino-2-naphthyl-phosphate-and-ammonia-borane-toward-ultrasensitive-and-simple-point-of-care-testing
#20
Jeongwook Seo, Hyeri Ha, Seonhwa Park, Al-Monsur Jiaul Haque, Sinyoung Kim, Jung Min Joo, Haesik Yang
Biosensors for ultrasensitive point-of-care testing require dried reagents with long-term stability and a high signal-to-background ratio. Although ortho-substituted diaromatic dihydroxy and aminohydroxy compounds undergo fast redox reactions, they are not used as electrochemical signaling species because they are readily oxidized and polymerized by dissolved oxygen. In this report, stable, solid 1-amino-2-naphthyl phosphate (1A2N-P) and ammonia-borane (H3N-BH3) are respectively employed as a substrate for alkaline phosphatase (ALP) and a reductant for electrochemical-chemical (EC) redox cycling...
August 25, 2017: ACS Sensors
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