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https://www.readbyqxmd.com/read/28104700/inhibition-of-4ebp-phosphorylation-mediates-the-cytotoxic-effect-of-mtor-kinase-inhibitors-in-aggressive-b-cell-lymphomas
#1
Chengfeng Bi, Xuan Zhang, Ting Lu, Xiaoyan Zhang, Xianhuo Wang, Bin Meng, Huilai Zhang, Ping Wang, Julie M Vose, Wing C Chan, Timothy W McKeithan, Kai Fu
Mechanistic target of rapamycin complex 1 (mTORC1) is a central integrator of nutrient and growth factor inputs that controls cell growth in eukaryotes. The second generation of mTOR kinase inhibitors (TORKi), directly targeting the mTOR catalytic site, are more effective than rapamycin and its analogs in cancer treatment, particularly in inducing apoptosis. However, the mechanism underlying the cytotoxic effect of TORKi remains elusive. Herein, we demonstrated that TORKi-induced apoptosis is predominantly dependent on loss of mTORC1-mediated 4EBP activation...
January 19, 2017: Haematologica
https://www.readbyqxmd.com/read/28100332/-expression-and-significance-of-mtor-4ebp1-hif-1%C3%AE-vegf-signaling-pathway-in-lung-tissues-of-asthmatic-mice
#2
Li Wang, Yan-Li Zhang, Xiu-Fang Wang, Zhe Song, Wei Wang
OBJECTIVE: To study the expression and significance of the mammalian target of rapamycin (mTOR)/eukaryote initiating factor 4E binding protein 1(4EBP1)/hypoxia inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) signaling pathway in asthmatic mice. METHODS: Forty SPF level 6-8 week-old female Balb/C mice were randomly divided into control, asthma, budesonide and mTOR inhibitor (rapamycin) intervention groups (n=10 each). The asthmatic mouse model was prepared via OVA induction and challenge test...
January 2017: Zhongguo Dang Dai Er Ke za Zhi, Chinese Journal of Contemporary Pediatrics
https://www.readbyqxmd.com/read/28088315/paris-saponin-induced-autophagy-promotes-breast-cancer-cell-apoptosis-via-the-akt-mtor-signaling-pathway
#3
Zhan-Zhi Xie, Man-Mei Li, Peng-Fei Deng, Sheng Wang, Lei Wang, Xue-Ping Lu, Liu-Bing Hu, Zui Chen, Hui-Yang Jie, Yi-Fei Wang, Xiao-Xiao Liu, Zhong Liu
Paris saponins possess anticancer, anti-inflammatory, and antiviral effects. However, the anticancer effect of Paris saponins has not been well elucidated and the mechanisms underlying the potential function of Paris saponins in cancer therapy are needed to be further identify. In this study, we report that saponin compounds isolated from Paris polyphylla exhibited antitumor activity against breast cancer cell lines, MCF-7 and MDA-MB-231. Paris saponin XA-2 induced apoptosis in both cell lines, as evidenced by the activation of caspases and cleavage of Poly (ADP-ribose) polymerase...
January 11, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28078787/targeting-nasopharyngeal-carcinoma-by-artesunate-through-inhibiting-akt-mtor-and-inducing-oxidative-stress
#4
Qin Li, Wei Ni, Zhifeng Deng, Minghe Liu, Lazhi She, Qiong Xie
Drug repurposing has become an alternative therapeutic strategy for cancer treatment given the known pharmacokinetics and toxicity. The inhibitory effects of artesunate have been reported in various cancers. In this work, we investigated the effects of artesunate in nasopharyngeal carcinoma (NPC). We demonstrate that artesunate significantly inhibits proliferation via arresting NPC cells at G2/M phase. It also induces apoptosis through caspase-dependent and mitochondria-independent pathways in multiple NPC cell lines...
January 11, 2017: Fundamental & Clinical Pharmacology
https://www.readbyqxmd.com/read/28041982/4-nonylphenol-induces-autophagy-and-attenuates-mtor-p70s6k-4ebp1-signaling-by-modulating-ampk-activation-in-sertoli-cells
#5
Peng Duan, Chunhui Hu, Chao Quan, Tingting Yu, Wenting Huang, Wei Chen, Sha Tang, Yuqin Shi, Francis L Martin, Kedi Yang
The estrogenic chemical 4-nonylphenol (NP) is known to impair testicular devolopment and spermatogenesis in rodents. The objective of this study was to explore the effects of NP on autophagy induction and AMPK-mTOR signaling pathway in Sertoli cells (SCs), which are the "nursemaid cells" for meiosis of spermatocytes. In this study we exposed 7-week-old male rats to NP by intra-peritoneal injection at 0, 20, 50 or 100mg/kg body weight/2days for 20 consecutive days. Our results showed that exposure to NP dose-dependently induces the formation of autophagosomes in SCs, increases the expression of Beclin-1, the conversion of LC3-I to LC3-II and the mRNA expression of Atg3, Atg5, Atg7 and Atg12 in testis, and these effects are concomitant with the activation of AMPK, and the suppression of TSC2-mTOR-p70S6K/4EBP1 signaling cascade in testis...
December 29, 2016: Toxicology Letters
https://www.readbyqxmd.com/read/28026112/matrine-induces-akt-mtor-signalling-inhibition-mediated-autophagy-and-apoptosis-in-acute-myeloid-leukaemia-cells
#6
Junqing Wu, Gang Hu, Yuqing Dong, Ruye Ma, Zhijie Yu, Songfu Jiang, Yixiang Han, Kang Yu, Shenghui Zhang
Pharmacological modulation of autophagy has been referred to as a promising therapeutic strategy for cancer. Matrine, a main alkaloid extracted from Sophora flavescens Ait, has antitumour activity against acute myelocytic leukaemia (AML). Whether autophagy is involved in antileukaemia activity of matrine remains unobvious. In this study, we demonstrated that matrine inhibited cell viability and colony formation via inducing apoptosis and autophagy in AML cell lines HL-60, THP-1 and C1498 as well as primary AML cells...
December 27, 2016: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/27995363/unacylated-ghrelin-analog-prevents-myocardial-reperfusion-injury-independently-of-permeability-transition-pore
#7
Rania Harisseh, Bruno Pillot, Abdallah Gharib, Lionel Augeul, Noelle Gallo-Bona, René Ferrera, Joseph Loufouat, Thomas Delale, Soraya Allas, Thierry Abribat, Claire Crola Da Silva, Michel Ovize
Reperfusion injury is responsible for an important part of myocardial infarct establishment due notably to triggering cardiomyocytes death at the first minutes of reperfusion. AZP-531 is an optimized analog of unacylated ghrelin currently in clinical development in several metabolic diseases. We investigated a potential cardioprotective effect of AZP-531 in ischemia/reperfusion (IR) and the molecular underlying mechanism(s) involved in this protection. In vivo postconditioning with AZP-531 in C57BL6 mouse IR model decreased infarct size...
January 2017: Basic Research in Cardiology
https://www.readbyqxmd.com/read/27932243/inhibition-of-mtor-eif4e-by-anti-viral-drug-ribavirin-effectively-enhances-the-effects-of-paclitaxel-in-oral-tongue-squamous-cell-carcinoma
#8
Dehua Dai, Hujie Chen, Jing Tang, Yi Tang
Upregulation of eIF4E is associated with poor clinical outcome in many human cancers and represents a potential therapeutic target. However, the function of eIF4E remains unknown in oral tongue squamous cell carcinoma (OTSCC). In this work, we show that ribavirin, an anti-viral drug, effectively augments sensitivity of OTSCC cells to paclitaxel via inhibiting mTOR/eIF4E signaling pathway. Ribavirin dose-dependently inhibits proliferation and induces apoptosis in SCC-9 and CAL27 cells. Combination of ribavirin and paclitaxel are more effective in inhibiting proliferation and inducing apoptosis in OTSCC cells...
January 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27899988/mtor-downstream-effectors-4ebp1-and-eif4e-are-overexpressed-and-associated-with-hpv-status-in-precancerous-lesions-and-carcinomas-of-the-uterine-cervix
#9
Aristidis Asimomytis, Maria Karanikou, Alexander Rodolakis, Anna Vaiopoulou, Paraskevi Tsetsa, George Creatsas, Theodoros Stefos, Aristidis Antsaklis, Efstratios Patsouris, George Z Rassidakis
The present study aims to investigate the expression levels of two critical mammalian target of rapamycin (mTOR) downstream effectors, 4E binding protein 1 (4EBP1) and eukaryotic initiation factor 4E (eIF4E) proteins, in precancerous squamous intraepithelial lesions and cancer of the uterine cervix, and their association with human papilloma virus (HPV) infection status. Uterine cervical biopsies from 73 patients were obtained, including 40 fresh-frozen samples and 42 archival formalin-fixed, paraffin-embedded tissue specimens...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27888132/vitamin-e-deficiency-depressed-fish-growth-disease-resistance-and-the-immunity-and-structural-integrity-of-immune-organs-in-grass-carp-ctenopharyngodon-idella-referring-to-nf-%C3%AE%C2%BAb-tor-and-nrf2-signaling
#10
Jia-Hong Pan, Lin Feng, Wei-Dan Jiang, Pei Wu, Sheng-Yao Kuang, Ling Tang, Yong-An Zhang, Xiao-Qiu Zhou, Yang Liu
This study investigated the effects of dietary vitamin E on growth, disease resistance and the immunity and structural integrity of head kidney, spleen and skin in grass carp (Ctenopharyngodon idella). The fish were fed six diets containing graded levels of vitamin E (0, 45, 90, 135, 180 and 225 mg/kg diet) for 10 weeks. Subsequently, a challenge test was conducted by injection of Aeromonas hydrophila. The results showed that compared with optimal vitamin E supplementation, vitamin E deficiency caused depressed growth, poor survival rates and increased skin lesion morbidity in grass carp...
November 22, 2016: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/27832967/kinetic-modelling-of-in-vitro-data-of-pi3k-mtor1-pten-enzymes-and-on-target-inhibitors-rapamycin-bez235-and-ly294002
#11
Alexey Goltsov, Ghassan Tashkandi, Simon P Langdon, David J Harrison, James L Bown
The phosphatidylinositide 3-kinases (PI3K) and mammalian target of rapamycin-1 (mTOR1) are two key targets for anti-cancer therapy. Predicting the response of the PI3K/AKT/mTOR1 signalling pathway to targeted therapy is made difficult because of network complexities. Systems biology models can help explore those complexities but the value of such models is dependent on accurate parameterisation. Motivated by a need to increase accuracy in kinetic parameter estimation, and therefore the predictive power of the model, we present a framework to integrate kinetic data from enzyme assays into a unified enzyme kinetic model...
January 15, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/27779207/hbv-core-promoter-mutations-and-akt-upregulate-s-phase-kinase-associated-protein-2-to-promote-postoperative-hepatocellular-carcinoma-progression
#12
Lubiao Chen, Lin Gu, Yurong Gu, Hongbo Wang, Meihai Deng, Zania Stamataki, Ye Htun Oo, Yuehua Huang
Mutations in the hepatitis B virus (HBV) core promoter (CP) have been shown to be associated with hepatocellular carcinoma (HCC). The CP region overlaps HBV X gene, which activates AKT to regulate hepatocyte survival. However, the cooperation between these two cascades in HCC progression remains poorly understood. Here, we assayed virological factors and AKT expression in liver tissues from 56 HCC patients with better prognoses (BHCC, ≥5-year survival) and 58 with poor prognoses (PHCC, <5-year survival) after partial liver resection...
October 25, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27769069/non-immunosuppressive-triazole-based-small-molecule-induces-anticancer-activity-against-human-hormone-refractory-prostate-cancers-the-role-in-inhibition-of-pi3k-akt-mtor-and-c-myc-signaling-pathways
#13
Wohn-Jenn Leu, Sharada Prasanna Swain, She-Hung Chan, Jui-Ling Hsu, Shih-Ping Liu, Mei-Ling Chan, Chia-Chun Yu, Lih-Ching Hsu, Yen-Lin Chou, Wei-Ling Chang, Duen-Ren Hou, Jih-Hwa Guh
A series of triazole-based small molecules that mimic FTY720-mediated anticancer activity but minimize its immunosuppressive effect have been produced. SPS-7 is the most effective derivative displaying higher activity than FTY720 in anti-proliferation against human hormone-refractory prostate cancer (HRPC). It induced G1 arrest of cell cycle and subsequent apoptosis in thymidine block-mediated synchronization model. The data were supported by a decrease of cyclin D1 expression, a dramatic increase of p21 expression and an associated decrease in RB phosphorylation...
October 19, 2016: Oncotarget
https://www.readbyqxmd.com/read/27729552/impaired-coordination-between-signaling-pathways-is-revealed-in-human-colorectal-cancer-using-single-cell-mass-cytometry-of-archival-tissue-blocks
#14
Alan J Simmons, Cherié R Scurrah, Eliot T McKinley, Charles A Herring, Jonathan M Irish, M Kay Washington, Robert J Coffey, Ken S Lau
Cellular heterogeneity poses a substantial challenge to understanding tissue-level phenotypes and confounds conventional bulk analyses. To analyze signaling at the single-cell level in human tissues, we applied mass cytometry using cytometry time of flight to formalin-fixed, paraffin-embedded (FFPE) normal and diseased intestinal specimens. This technique, called FFPE-DISSECT (disaggregation for intracellular signaling in single epithelial cells from tissue), is a single-cell approach to characterizing signaling states in embedded tissue samples...
October 11, 2016: Science Signaling
https://www.readbyqxmd.com/read/27699948/reduced-phosphorylation-of-ribosomal-protein-s6-is-associated-with-sensitivity-to-mek-inhibition-in-gastric-cancer-cells
#15
Yuka Hirashita, Yoshiyuki Tsukamoto, Kazuyoshi Yanagihara, Shoichi Fumoto, Naoki Hijiya, Chisato Nakada, Tomohisa Uchida, Keiko Matsuura, Masaaki Kodama, Tadayoshi Okimoto, Tsutomu Daa, Masataka Seike, Hidekatsu Iha, Kuniaki Shirao, Kazunari Murakami, Masatsugu Moriyama
Gastric cancer (GC) is characterized by amplifications of receptor tyrosine kinases (RTK) and KRAS, therefore, targeting of the RTK/KRAS downstream pathways could help to broaden the applicability of molecular targeted therapy for GC. We assembled a panel of 48 GC cell lines and screened predictors of responsiveness to inhibition of the RAF/MEK/ERK pathway, one of the RTK/KRAS downstream pathways. We found that GC cells with MET amplification or KRAS mutation, but not amplification, tended to be sensitive to MEK inhibition...
December 2016: Cancer Science
https://www.readbyqxmd.com/read/27650250/effects-of-high-epa-and-high-dha-fish-oils-on-changes-in-signaling-associated-with-protein-metabolism-induced-by-hindlimb-suspension-in-rats
#16
Gabriel Nasri Marzuca-Nassr, Kaio Fernando Vitzel, Luís Gustavo De Sousa, Gilson M Murata, Amanda Rabello Crisma, Carlos Flores Rodrigues Junior, Phablo Abreu, Rosângela Pavan Torres, Jorge Mancini-Filho, Sandro M Hirabara, Philip Newsholme, Rui Curi
The effects of either eicosapentaenoic (EPA)- or docosahexaenoic (DHA)-rich fish oils on hindlimb suspension (HS)-induced muscle disuse atrophy were compared. Daily oral supplementations (0.3 mL/100 g b.w.) with mineral oil (MO) or high EPA or high DHA fish oils were performed in adult rats. After 2 weeks, the animals were subjected to HS for further 2 weeks. The treatments were maintained alongside HS At the end of 4 weeks, we evaluated: body weight gain, muscle mass and fat depots, composition of fatty acids, cross-sectional areas (CSA) of the soleus muscle and soleus muscle fibers, activities of cathepsin L and 26S proteasome, and content of carbonylated proteins in the soleus muscle...
September 2016: Physiological Reports
https://www.readbyqxmd.com/read/27624100/leucine-supplementation-stimulates-protein-synthesis-and-reduces-degradation-signal-activation-in-muscle-of-newborn-pigs-during-acute-endotoxemia
#17
Adriana D Hernandez-García, Daniel A Columbus, Rodrigo Manjarín, Hanh V Nguyen, Agus Suryawan, Renán A Orellana, Teresa A Davis
Sepsis disrupts skeletal muscle proteostasis and mitigates the anabolic response to leucine (Leu) in muscle of mature animals. We have shown that Leu stimulates muscle protein synthesis (PS) in healthy neonatal piglets. To determine if supplemental Leu can stimulate PS and reduce protein degradation (PD) signaling in neonatal muscle during endotoxemia, overnight-fasted neonatal pigs were infused for 8 h with LPS or saline while plasma amino acids, glucose, and insulin were maintained at fasting levels during pancreatic-substrate clamps...
October 1, 2016: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/27618686/proline-starvation-induces-unresolved-er-stress-and-hinders-mtorc1-dependent-tumorigenesis
#18
Nisebita Sahu, Darlene Dela Cruz, Min Gao, Wendy Sandoval, Peter M Haverty, Jinfeng Liu, Jean-Philippe Stephan, Benjamin Haley, Marie Classon, Georgia Hatzivassiliou, Jeff Settleman
The role of essential amino acids in metabolic reprogramming of cancer cells is now well established, whereas the role of non-essential amino acids (NEAAs) in malignancy remains less clear. Here, we have identified an important role for the NEAA proline in the tumorigenic potential of a subset of cancer cells. By profiling a large panel of cancer cell lines, we observed that proline consumption and expression of proline biosynthesis enzymes were well correlated with clonogenic and tumorigenic potential. Moreover, proline starvation or inhibition of proline biosynthesis enzymes impaired clonogenic/tumorigenic potential...
September 3, 2016: Cell Metabolism
https://www.readbyqxmd.com/read/27613409/gcn2-and-eif2%C3%AE-phosphorylation-independent-but-atf4-dependent-induction-of-care-containing-genes-in-methionine-deficient-cells
#19
Kevin M Mazor, Martha H Stipanuk
Amino-acid deprivation is sensed by the eIF2α kinase GCN2. Under conditions of essential amino-acid limitation, GCN2 phosphorylates eIF2α, inhibiting the formation of a new ternary complex and hence mRNA translation initiation. While decreasing global mRNA translation, eIF2α phosphorylation also increases the translation of the integrated stress response (ISR) transcription factor ATF4, which increases the expression of many stress response genes that contain a C/EBP-ATF response element (CARE), including Atf4, 4Ebp1, Asns, and Chop...
December 2016: Amino Acids
https://www.readbyqxmd.com/read/27613305/decreased-activation-of-placental-mtor-family-members-is-associated-with-the-induction-of-intrauterine-growth-restriction-by-secondhand-smoke-in-the-mouse
#20
Camilo Mejia, Josh Lewis, Clinton Jordan, Juan Mejia, Connor Ogden, Troy Monson, Duane Winden, Marc Watson, Paul R Reynolds, Juan A Arroyo
Cigarette smoke is known to be a risk for the development of intrauterine growth restriction (IUGR). Our objective was to assess the effects of secondhand smoke (SHS) during pregnancy and to what extent it regulates the activation of mTOR family members and murine trophoblast invasion. Mice were treated to SHS for 4 days. Placental and fetal weights were recorded at the time of necropsy. Immunohistochemistry was used to determine the level of placental trophoblast invasion. Western blots were utilized to assess the activation of caspase 3, XIAP, mTOR, p70 and 4EBP1 in treated and control placental lysates...
September 9, 2016: Cell and Tissue Research
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