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https://www.readbyqxmd.com/read/29775995/phosphorylation-alters-bim-mediated-mcl-1-stabilization-and-priming
#1
Jason E Conage-Pough, Lawrence H Boise
Mcl-1 is a highly labile protein, subject to extensive posttranslational regulation. This distinguishes Mcl-1 from other anti-apoptotic proteins and necessitates further study to better understand how interactions with pro-apoptotic Bcl-2 proteins affect its regulation. One such protein, Bim, is known to stabilize Mcl-1, and Bim phosphorylation has been associated with increased Mcl-1 binding. Consequently, we investigated the potential impact of Bim phosphorylation on Mcl-1 stability. We found that Bim stabilizes and primes Mcl-1 in RPCI-WM1 cells and is constitutively phosphorylated...
May 18, 2018: FEBS Journal
https://www.readbyqxmd.com/read/29769260/bim-regulates-the-survival-and-suppressive-capability-of-cd8-foxp3-regulatory-t-cells-during-murine-gvhd
#2
Kimberle Agle, Benjamin G Vincent, Clint Piper, Ludovic Belle, Vivian Zhou, Warren Shlomchik, Jonathan S Serody, William R Drobyski
CD8+ Foxp3+ T cells (Tregs) are a potent regulatory population whose functional and ontological similarities to CD4+ Fox3+ T cells have not been well delineated. Using an experimental model of graft versus host disease (GVHD), we observed that CD8+ Tregs were significantly less potent than CD4+ Tregs for the suppression of GVHD. To define the mechanistic basis for this observation, we examined the T cell repertoire and the transcriptional profile of in vivo-derived CD4+ and CD8+ Tregs that emerged early during this disease...
May 16, 2018: Blood
https://www.readbyqxmd.com/read/29767411/mek1-2-inhibition-by-binimetinib-is-effective-as-a-single-agent-and-potentiates-the-actions-of-venetoclax-and-abt-737-under-conditions-that-mimic-the-chronic-lymphocytic-leukaemia-cll-tumour-microenvironment
#3
Kyle Crassini, Yandong Shen, William S Stevenson, Richard Christopherson, Chris Ward, Stephen P Mulligan, O Giles Best
The survival and proliferation of chronic lymphocytic leukaemia (CLL) cells is driven by multiple signalling pathways, including those mediated by the B cell, Toll-like and chemokine receptors. Many of these pathways converge on the same signalling molecules, including those involved in the Raf-1/MEK/Erk1/2-MAPK pathway. We investigated the effects of the MEK1/2 (also termed MAP2K1/2) inhibitor, binimetinib, against CLL cells cultured under conditions that mimic aspects of the tumour microenvironment. Binimetinib blocked CLL cell survival induced by stroma-conditioned media and phorbol myristylate (PMA)...
May 16, 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29764852/combined-hdac-and-bromodomain-protein-inhibition-reprograms-tumor-cell-metabolism-and-elicits-synthetic-lethality-in-glioblastoma
#4
Yiru Zhang, Chiaki Tsuge Ishida, Wataru Ishida, Sheng-Fu L Lo, Junfei Zhao, Chang Shu, Elena Bianchetti, Giulio Kleiner, Maria Sanchez-Quintero, Catarina M Quinzii, Mike-Andrew Westhoff, Georg Karpel-Massler, Peter Canoll, Markus D Siegelin
PURPOSE: Glioblastoma remain a challenge in oncology in part due to tumor heterogeneity. EXPERIMENTAL DESIGN: Patient-derived xenograft and stem-like glioblastoma cells were used as the primary model systems. RESULTS: Based on a transcriptome and subsequent gene set enrichment analysis (GSEA), we show by using clinically validated compounds that combined histone deacetylase (HDAC) inhibition and Bromodomain protein (BRD) inhibition results in pronounced synergistic reduction in cellular viability in patient-derived xenograft and stem-like glioblastoma cells...
May 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29762232/modified-exosomes-reduce-apoptosis-and-ameliorate-neural-deficits-induced-by-traumatic-brain-injury
#5
Bo Wang, Shuangshuang Han
Apoptosis contributes to the pathogenesis of traumatic brain injury (TBI). Engineered exosomes incorporated with therapeutic nuclear acids have been explored for gene therapy for human diseases. The current study sought to investigate the effect of modified exosome-containing plasmids expressing B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X-protein (Bax) shRNA on apoptosis and neural functions after TBI. C57BL/6J mice were subjected to controlled cortical impact injury and were treated with the modified exosomes...
May 11, 2018: ASAIO Journal: a Peer-reviewed Journal of the American Society for Artificial Internal Organs
https://www.readbyqxmd.com/read/29761903/the-combination-of-a-sphingosine-kinase-2-inhibitor-abc294640-and-a-bcl-2-inhibitor-abt-199-displays-synergistic-anti-myeloma-effects-in-myeloma-cells-without-a-t-11-14-translocation
#6
Pasupathi Sundaramoorthy, Cristina Gasparetto, Yubin Kang
Multiple myeloma (MM) remains an incurable disease in need of the development of novel therapeutic agents and drug combinations. ABT-199 is a specific Bcl-2 inhibitor in clinical trials for MM; however, its activity as a single agent was limited to myeloma patients with the t(11;14) translocation who acquire resistance due to co-expression of Mcl-1 and Bcl-xL. These limitations preclude its use in a broader patient population. We have recently found that a sphingosine kinase 2-specific inhibitor (ABC294640) induces apoptosis in primary human CD138+ cells and MM cell lines...
May 15, 2018: Cancer Medicine
https://www.readbyqxmd.com/read/29760958/targeting-muc1-c-suppresses-bcl2a1-in-triple-negative-breast-cancer
#7
Masayuki Hiraki, Takahiro Maeda, Neha Mehrotra, Caining Jin, Maroof Alam, Audrey Bouillez, Tsuyoshi Hata, Ashujit Tagde, Amy Keating, Surender Kharbanda, Harpal Singh, Donald Kufe
B-cell lymphoma 2-related protein A1 (BCL2A1) is a member of the BCL-2 family of anti-apoptotic proteins that confers resistance to treatment with anti-cancer drugs; however, there are presently no agents that target BCL2A1. The MUC1-C oncoprotein is aberrantly expressed in triple-negative breast cancer (TNBC) cells, induces the epithelial-mesenchymal transition (EMT) and promotes anti-cancer drug resistance. The present study demonstrates that targeting MUC1-C genetically and pharmacologically in TNBC cells results in the downregulation of BCL2A1 expression...
2018: Signal Transduction and Targeted Therapy
https://www.readbyqxmd.com/read/29749435/spag6-silencing-induces-apoptosis-in-the-myelodysplastic-syndrome-cell-line-skm%C3%A2-1-via-the-pten-pi3k-akt-signaling-pathway-in-vitro-and-in-vivo
#8
Jiaxiu Yin, Xinxin Li, Zaili Zhang, Xiaohua Luo, Li Wang, Lin Liu
Apoptosis is a multi-step mechanism of cell self‑destruction for maintaining cellular homeostatic balance. Accumulating evidence indicates that abnormal apoptosis promotes the evolution and progression of myelodysplastic syndromes (MDS). As a novel cancer-testis antigen, sperm‑associated antigen 6 (SPAG6) has been reported to regulate apoptosis through the tumor necrosis factor-related apoptosis-inducing ligand signaling pathway in the MDS cell line SKM‑1. However, the mechanism of the intrinsic cell death pathway for apoptosis induction by SPAG6 silencing is unclear...
May 2, 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29748606/cd47-ligation-induced-cell-death-in-t-acute-lymphoblastic-leukemia
#9
Pascal Leclair, Chi-Chao Liu, Mahdis Monajemi, Gregor S Reid, Laura M Sly, Chinten James Lim
CD47 is a cell-surface marker well recognized for its anti-phagocytic functions. As such, an emerging avenue for targeted cancer therapies involves neutralizing the anti-phagocytic function using monoclonal antibodies (mAbs) to enhance tumour cell immunogenicity. A lesser known consequence of CD47 receptor ligation is the direct induction of tumour cell death. While several mAbs and their derivatives with this property have been studied, the best characterized is the commercially available mAb B6H12, which requires immobilization for induction of cell death...
May 10, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29743589/dual-inhibition-of-bcl-xl-and-mcl-1-is-required-to-induce-tumour-regression-in-lung-squamous-cell-carcinomas-sensitive-to-fgfr-inhibition
#10
Clare E Weeden, Casey Ah-Cann, Aliaksei Z Holik, Julie Pasquet, Jean-Marc Garnier, Delphine Merino, Guillaume Lessene, Marie-Liesse Asselin-Labat
Genetic alterations in the fibroblast growth factor receptors (FGFRs) have been described in multiple solid tumours including bladder cancer, head and neck and lung squamous cell carcinoma (SqCC). However, recent clinical trials showed limited efficacy of FGFR-targeted therapy in lung SqCC, suggesting combination therapy may be necessary to improve patient outcomes. Here we demonstrate that FGFR therapy primes SqCC for cell death by increasing the expression of the pro-apoptotic protein BIM. We therefore hypothesised that combining BH3-mimetics, potent inhibitors of pro-survival proteins, with FGFR-targeted therapy may enhance the killing of SqCC cells...
May 10, 2018: Oncogene
https://www.readbyqxmd.com/read/29743557/inhibition-of-bcl-2-bcl-xl-and-c-met-causes-synthetic-lethality-in-model-systems-of-glioblastoma
#11
Yiru Zhang, Chiaki Tsuge Ishida, Chang Shu, Giulio Kleiner, Maria J Sanchez-Quintero, Elena Bianchetti, Catarina M Quinzii, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D Siegelin
Recent data suggest that glioblastomas (GBM) activate the c-MET signaling pathway and display increased levels in anti-apoptotic Bcl-2 family members. Therefore, targeting these two deregulated pathways for therapy might yield synergistic treatment responses. We applied extracellular flux analysis to assess tumor metabolism. We found that combined treatment with ABT263 and Crizotinib synergistically reduces the proliferation of glioblastoma cells, which was dependent on dual inhibition of Bcl-2 and Bcl-xL. The combination treatment led to enhanced apoptosis with loss of mitochondrial membrane potential and activation of caspases...
May 9, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29741767/down-regulation-of-intracellular-anti-apoptotic-proteins-particularly-c-flip-by-therapeutic-agents-the-novel-view-to-overcome-resistance-to-trail
#12
REVIEW
Ali Hassanzadeh, Majid Farshdousti Hagh, Mohammad Reza Alivand, Ali Akbar Movassaghpour Akbari, Karim Shams Asenjan, Raedeh Saraei, Saeed Solali
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or Apo2L) is a member of the tumor necrosis factor (TNF) superfamily that induces apoptosis in different types of cancer cells via activation of caspase cascade. TRAIL interacts with its cognate receptors that placed on cancer cells surface, including TRAIL-R1 (death receptor 4, DR4), TRAIL-R2 (death receptor 5, DR5), TRAIL-R3 (decoy receptor 1, DcR1), TRAIL-R4 (decoy receptor 2, DcR2), and osteoprotegerin (OPG). Despite high apoptosis-inducing ability of TRAIL, various cancerous cells gain resistance to TRAIL gradually, and consequently TRAIL potential for apoptosis stimulation in these cells diminishes intensely...
May 9, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29740433/syk-inhibition-induces-apoptosis-in-germinal-center-like-b-cells-by-modulating-the-antiapoptotic-protein-myeloid-cell-leukemia-1-affecting-b-cell-activation-and-antibody-production
#13
Nathalie Roders, Florence Herr, Gorbatchev Ambroise, Olivier Thaunat, Alain Portier, Aimé Vazquez, Antoine Durrbach
B cells play a major role in the antibody-mediated rejection (AMR) of solid organ transplants, a major public health concern. The germinal center (GC) is involved in the generation of donor-specific antibody-producing plasma cells and memory B cells, which are often poorly controlled by current treatments. Myeloid cell leukemia-1 (Mcl-1), an antiapoptotic member of the B-cell lymphoma-2 family, is essential for maintenance of the GC reaction and B-cell differentiation. During chronic AMR (cAMR), tertiary lymphoid structures resembling GCs appear in the rejected organ, suggesting local lymphoid neogenesis...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29738775/crl4b-rbbp7-targets-huwe1-for-ubiquitination-and-proteasomal-degradation
#14
Fei Liu, Li Cao, Ting Zhang, Fen Chang, Yongjie Xu, Qin Li, Jingcheng Deng, Li Li, Genze Shao
The E3 ubiquitin ligase HUWE1/Mule/ARF-BP1 plays an important role in diverse biological processes including DNA damage repair and apoptosis. Our previous study has shown that in response to DNA damage HUWE1 was downregulated in CUL4B-mediated ubiquitination and subsequent proteasomal degradation, and CUL4B-mediated regulation of HUWE1 is important for cell survival upon DNA damage. CUL4B is a core component of the CUL4B Ring ligase complexes containing ROC1, DDB1 and a DDB1-Cullin Associated Factors (DCAFs), the latter of which are DDB1-binding WD40 adaptors critical for substrate recognition and recruitment...
May 5, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29735440/-chloroquine-induces-apoptosis-of-human-hepatocellular-carcinoma-cells-in-vitro-by-mir-26b-mediated-regulation-of-mcl-1
#15
Xiao-Jin Sun, Lin-Yan Ma, Meng-Xiao Zhang, Ying Wang, Pei Zhang, Chen-Chen Jiang, Hao Liu
OBJECTIVE: To investigate the effect of chloroquine in inducing apoptosis of human hepatocellular carcinoma cells and explore the possible mechanism. METHODS: MTT assay and flow cytometry were used to evaluate chloroquine-induced growth inhibition and apoptosis in human hepatocellular carcinoma HepG2 cells, respectively. The ATP levels in chloroquine-treated cells were detected using an ATP assay kit. PCR and Western blotting were used to detect the expression levels of miR-26b and Mcl-1 in the cells, respectively...
April 20, 2018: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
https://www.readbyqxmd.com/read/29734677/the-effect-of-bornyl-cis-4-hydroxycinnamate-on-melanoma-cell-apoptosis-is-associated-with-mitochondrial-dysfunction-and-endoplasmic-reticulum-stress
#16
Tzu-Yen Yang, Yu-Jen Wu, Chi-I Chang, Chien-Chih Chiu, Mei-Li Wu
Bornyl cis -4-hydroxycinnamate, an active compound isolated from Piper betle stems, was investigated in terms of its effects on A2058 and A375 melanoma cell proliferation and protein expression in this study. We used flow cytometric analysis to examine the early stages of apoptosis induced by bornyl cis -4-hydroxycinnamate in the two melanoma cell lines and employed comparative proteomic analysis to investigate the effects of this compound on protein expression in A375 cells. Master maps generated by PDQuest software from two-dimensional electrophoresis (2-DE) analysis of A375 cells showed that the expression levels of 35 proteins were significantly altered, with 18 proteins upregulated and 17 downregulated...
May 4, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29732004/s55746-is-a-novel-orally-active-bcl-2-selective-and-potent-inhibitor-that-impairs-hematological-tumor-growth
#17
Patrick Casara, James Davidson, Audrey Claperon, Gaëtane Le Toumelin-Braizat, Meike Vogler, Alain Bruno, Maïa Chanrion, Gaëlle Lysiak-Auvity, Thierry Le Diguarher, Jérôme-Benoît Starck, Ijen Chen, Neil Whitehead, Christopher Graham, Natalia Matassova, Pawel Dokurno, Christopher Pedder, Youzhen Wang, Shumei Qiu, Anne-Marie Girard, Emilie Schneider, Fabienne Gravé, Aurélie Studeny, Ghislaine Guasconi, Francesca Rocchetti, Sophie Maïga, Jean-Michel Henlin, Frédéric Colland, Laurence Kraus-Berthier, Steven Le Gouill, Martin J S Dyer, Roderick Hubbard, Mike Wood, Martine Amiot, Gerald M Cohen, John A Hickman, Erick Morris, James Murray, Olivier Geneste
Escape from apoptosis is one of the major hallmarks of cancer cells. The B-cell Lymphoma 2 (BCL-2) gene family encodes pro-apoptotic and anti-apoptotic proteins that are key regulators of the apoptotic process. Overexpression of the pro-survival member BCL-2 is a well-established mechanism contributing to oncogenesis and chemoresistance in several cancers, including lymphoma and leukemia. Thus, BCL-2 has become an attractive target for therapeutic strategy in cancer, as demonstrated by the recent approval of ABT-199 (Venclexta™) in relapsed or refractory Chronic Lymphocytic Leukemia with 17p deletion...
April 13, 2018: Oncotarget
https://www.readbyqxmd.com/read/29730957/homeostasis-apoptosis-and-cell-cycle-in-normal-and-pathological-prostate
#18
Norelia Torrealba, Gonzalo Rodríguez-Berriguete, Raúl Vera, Benito Fraile, Gabriel Olmedilla, Pilar Martínez-Onsurbe, Manuel Sánchez-Chapado, Ricardo Paniagua, Mar Royuela
Prostatic diseases such as hyperplasia and cancer are a consequence of glandular aging due to the loss of homeostasis. Glandular homeostasis is guaranteed by the delicate balance between production and cell death. Both cell renewal and apoptosis are part of this delicate balance. We will explore the predictive capacity for biochemical progression, following prostatectomy, of some members of the Bcl-2 family and of proteins involved in cell cycle inhibition in conjunction with established classical markers. The expression of Bcl-2, Bcl-xL, Mcl-1, Bax, Bim, Bad, PUMA, Noxa, p21, p27, Rb and p53 were analyzed by immunochemistry in 86 samples of radical prostatectomy and correlated with each of the markers established clinicopathological tests using statistical tests such as Sperman, Kaplan-Meier curves, unifactorial Cox, and multifactorial...
May 6, 2018: Aging Male: the Official Journal of the International Society for the Study of the Aging Male
https://www.readbyqxmd.com/read/29723246/early-changes-in-rps6-phosphorylation-and-bh3-profiling-predict-response-to-chemotherapy-in-aml-cells
#19
Martin Grundy, Thomas Jones, Liban Elmi, Michael Hall, Adam Graham, Nigel Russell, Monica Pallis
Blasts from different patients with acute myeloid leukemia (AML) vary in the agent(s) to which they are most responsive. With a myriad of novel agents to evaluate, there is a lack of predictive biomarkers to precisely assign targeted therapies to individual patients. Primary AML cells often survive poorly in vitro, thus confounding conventional cytotoxicity assays. The purpose of this work was to assess the potential of two same-day functional predictive assays in AML cell lines to predict long-term response to chemotherapy...
2018: PloS One
https://www.readbyqxmd.com/read/29719597/microrna-193b-3p-represses-neuroblastoma-cell-growth-via-downregulation-of-cyclin-d1-mcl-1-and-mycn
#20
Sarah Andrea Roth, Øyvind H Hald, Steffen Fuchs, Cecilie Løkke, Ingvild Mikkola, Trond Flægstad, Johannes Schulte, Christer Einvik
Neuroblastoma is the most common diagnosed tumor in infants and the second most common extracranial tumor of childhood. The survival rate of patients with high-risk neuroblastoma is still very low despite intensive multimodal treatments. Therefore, new treatment strategies are needed. In recent years, miRNA-based anticancer therapy has received growing attention. Advances in this novel treatment strategy strongly depends on the identification of candidate miRNAs with broad-spectrum antitumor activity. Here, we identify miR-193b as a miRNA with tumor suppressive properties...
April 6, 2018: Oncotarget
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