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https://www.readbyqxmd.com/read/29146887/targeted-therapy-of-gastroenteropancreatic-neuroendocrine-tumours-preclinical-strategies-and-future-targets
#1
Elke Tatjana Aristizabal Prada, Christoph J Auernhammer
Molecular targeted therapy of advanced neuroendocrine tumours (NETs) of the gastroenteropancreatic (GEP) system currently encompasses approved therapy with the mTOR-inhibitor everolimus and the multi-tyrosinkinase inhibitor sunitinib. However clinical efficacy of these treatment strategies is limited by low objective response rates and limited progression free survival due to tumor resistance. Further novel strategies for molecular targeted therapy of NETs of the GEP-system are needed. This paper reviews preclinical research models and signaling pathways in NETs of the GEP-system...
November 16, 2017: Endocrine Connections
https://www.readbyqxmd.com/read/29143563/mammalian-target-of-rapamycin-complex-2-mtorc2-controls-glycolytic-gene-expression-by-regulating-histone-h3-lysine-56-acetylation
#2
Raghavendra Vadla, Devyani Haldar
Metabolic reprogramming is a hallmark of cancer cells, but the mechanisms are not well understood. The mammalian target of rapamycin complex 2 (mTORC2) controls cell growth and proliferation and plays a critical role in metabolic reprogramming in glioma. mTORC2 regulates cellular processes such as cell survival, metabolism, and proliferation by phosphorylation of AGC kinases. Components of mTORC2 are shown to localize to the nucleus, but whether mTORC2 modulates epigenetic modifications to regulate gene expression is not known...
November 16, 2017: Cell Cycle
https://www.readbyqxmd.com/read/29143288/gsk3%C3%AE-controls-mtor-and-prosurvival-signaling-in-neurons
#3
Malgorzata Urbanska, Agata Gozdz, Matylda Macias, Iwona A Cymerman, Ewa Liszewska, Ilona Kondratiuk, Herman Devijver, Benoit Lechat, Fred Van Leuven, Jacek Jaworski
Glycogen synthase kinases-3β (GSK3β) is a key regulator of cell homeostasis. In neurons, GSK3β contributes to control of neuronal transmission and plasticity. Despite extensive studies in non-neuronal cells, crosstalk between GSK3β and other signaling pathways remains not well defined in neurons. In the present study, we report that GSK3β positively affected the activity of effectors of mammalian target of rapamycin complex 1 (mTORC1) and complex 2 (mTORC2), in mature neurons in vitro and in vivo. GSK3β also promoted prosurvival signaling and attenuated kainic acid-induced apoptosis...
November 15, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/29137241/erk-inhibition-sensitizes-cz415-induced-anti-osteosarcoma-activity-in-vitro-and-in-vivo
#4
Gang Yin, Jin Fan, Wei Zhou, Qingfeng Ding, Jun Zhang, Xuan Wu, Pengyu Tang, Hao Zhou, Bowen Wan, Guoyong Yin
mTOR is a valuable oncotarget for osteosarcoma. The anti-osteosarcoma activity by a novel mTOR kinase inhibitor, CZ415, was evaluated. We demonstrated that CZ415 potently inhibited survival and proliferation of known osteosarcoma cell lines (U2OS, MG-63 and SaOs2), and primary human osteosarcoma cells. Further, CZ415 provoked apoptosis and disrupted cell cycle progression in osteosarcoma cells. CZ415 treatment in osteosarcoma cells concurrently blocked mTORC1 and mTORC2 activation. Intriguingly, ERK-MAPK activation could be a major resistance factor of CZ415...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29121714/everolimus-plus-ku0063794-regimen-promotes-anticancer-effects-against-hepatocellular-carcinoma-cells-through-the-paradoxical-inhibition-of-autophagy
#5
Sang Chul Lee, Kee-Hwan Kim, Ok-Hee Kim, Sang Kuon Lee, Ha-Eun Hong, Byung Jo Choi, Wonjun Jeong, Say-June Kim
Purpose: Everolimus only inhibits mammalian target of rapamycin complex 1 (mTORC1), whereas Ku0063794 inhibits both mTORC1 and mTORC2. Although they have similar anticancer effects, their combination has a synergistic effect against hepatocellular carcinoma (HCC) cells. We aimed to determine the mechanism underlying the synergistic effects of everolimus and Ku0063794 associated with autophagy in HCC cells. Materials and Methods: We compared the effects of everolimus and Ku0063794, individually or in combination, on both the in vitro and in vivo models of HCCs...
November 9, 2017: Cancer Research and Treatment: Official Journal of Korean Cancer Association
https://www.readbyqxmd.com/read/29100733/synthesis-antifungal-and-antitumor-activity-of-two-new-types-of-imidazolin-2-ones
#6
Shaopeng Wei, Li Li, Yaping Shu, Kun Zhao, Zhiqin Ji
Thirty-six imidazolin-2-ones, including ten pairs of benzimidazolones and sixteen imidazopyridines, were synthesized and subjected for the evaluation of antifungal and antitumor activity. Compounds 4a-01, 6-01, 6-04 and 6-06 could effectively inhibit the spore germination and mycelium growth of Botrytis cinerea. The relationship between structure and antifungal activity revealed that the introducing short-chain aliphatic acyl groups at the moiety of imidazopyridines is favorable for the antifungal activity, whereas aromatic acyl groups are much better than aliphatic acyl groups for the activity of benzimidazolones except for acetyl...
October 21, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29080085/dual-mtorc1-mtorc2-blocker-as-a-possible-therapy-for-tauopathy-in-cellular-model
#7
Mohamed Salama, Mahmoud Elhussiny, Alshimaa Magdy, Ahmed G Omran, Aziza Alsayed, Ramy Ashry, Wael Mohamed
Tauopathy comprises a group of disorders caused by abnormal aggregates of tau protein. In these disorders phosphorylated tau protein tends to accumulate inside neuronal cells (soma) instead of the normal axonal distribution of tau. A suggested therapeutic strategy for tauopathy is to induce autophagy to increase the ability to get rid of the unwanted tau aggregates. One of the key controllers of autophagy is mTOR. Blocking mTOR leads to stimulation of autophagy. Recently, unravelling molecular structure of mTOR showed that it is formed of two subunits: mTORC1/C2...
October 27, 2017: Metabolic Brain Disease
https://www.readbyqxmd.com/read/29080043/pi3k-akt-mtor-pathway-involvement-in-regulating-growth-hormone-secretion-in-a-rat-pituitary-adenoma-cell-line
#8
Carmelina Di Pasquale, Erica Gentilin, Simona Falletta, Mariaenrica Bellio, Mattia Buratto, Ettore Degli Uberti, Maria Chiara Zatelli
PURPOSE: Insulin-like growth factor 1 (IGF1) controls growth hormone (GH) secretion via a negative feed-back loop that may disclose novel mechanisms possibly useful to control GH hyper-secretion. Our aim was to understand whether PI3K/Akt/mTOR pathway is involved in IGF1 negative feedback on GH secretion. METHODS: Cell viability, GH secretion, Akt, and Erk 1/2 phosphorylation levels in the rat GH3 cell line were assessed under treatment with IGF1 and/or everolimus, an mTOR inhitior...
October 27, 2017: Endocrine
https://www.readbyqxmd.com/read/29078414/twenty-five-years-of-mtor-uncovering-the-link-from-nutrients-to-growth
#9
David M Sabatini
In my PNAS Inaugural Article, I describe the development of the mTOR field, starting with efforts to understand the mechanism of action of the drug rapamycin, which ∼25 y ago led to the discovery of the mTOR protein kinase. I focus on insights that we have contributed and on work that has been particularly influential to me, as well as provide some personal reflections and stories. We now appreciate that, as part of two distinct complexes, mTORC1 and mTORC2, mTOR is the major regulator of growth (mass accumulation) in animals and is the key link between the availability of nutrients in the environment and the control of most anabolic and catabolic processes...
October 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29077243/dual-inhibition-of-the-mtorc1-and-mtorc2-signaling-pathways-is-a-promising-therapeutic-target-for-adult-t-cell-leukemia
#10
Takahito Kawata, Kohei Tada, Masayuki Kobayashi, Takashi Sakamoto, Yoko Takiuchi, Fumie Iwai, Maki Sakurada, Masakatsu Hishizawa, Kotaro Shirakawa, Keisuke Shindo, Hironori Sato, Akifumi Takaori-Kondo
ATL has a poor prognosis due to severe immunosuppression and rapid tumor progression with resistance to conventional chemotherapy. Recent integrated-genome analysis has revealed mutations in many genes involved in the T-cell signaling pathway, suggesting that the aberration of this pathway is an important factor in ATL pathogenesis and ATL-cell proliferation. We screened a siRNA library to examine signaling-pathway functionality and found that the PI3K/Akt/mTOR pathway is critical to ATL-cell proliferation...
October 27, 2017: Cancer Science
https://www.readbyqxmd.com/read/29077002/the-role-of-mammalian-target-of-rapamycin-mtor-in-insulin-signaling
#11
REVIEW
Mee-Sup Yoon
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that controls a wide spectrum of cellular processes, including cell growth, differentiation, and metabolism. mTOR forms two distinct multiprotein complexes known as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which are characterized by the presence of raptor and rictor, respectively. mTOR controls insulin signaling by regulating several downstream components such as growth factor receptor-bound protein 10 (Grb10), insulin receptor substrate (IRS-1), F-box/WD repeat-containing protein 8 (Fbw8), and insulin like growth factor 1 receptor/insulin receptor (IGF-IR/IR)...
October 27, 2017: Nutrients
https://www.readbyqxmd.com/read/29074727/liver-reptin-ruvbl2-controls-glucose-and-lipid-metabolism-with-opposite-actions-on-mtorc1-and-mtorc2-signalling
#12
Joaquim Javary, Nathalie Allain-Courtois, Nicolas Saucisse, Pierre Costet, Capucine Heraud, Fadila Benhamed, Rémi Pierre, Corinne Bure, Nestor Pallares-Lupon, Marcio Do Cruzeiro, Catherine Postic, Daniela Cota, Pierre Dubus, Jean Rosenbaum, Samira Benhamouche-Trouillet
OBJECTIVE: The AAA+ ATPase Reptin is overexpressed in hepatocellular carcinoma and preclinical studies indicate that it could be a relevant therapeutic target. However, its physiological and pathophysiological roles in vivo remain unknown. This study aimed to determine the role of Reptin in mammalian adult liver. DESIGN AND RESULTS: We generated an inducible liver-specific Reptin knockout (Repin(LKO) ) mouse model. Following Reptin invalidation, mice displayed decreased body and fat mass, hypoglycaemia and hypolipidaemia...
October 26, 2017: Gut
https://www.readbyqxmd.com/read/29072256/rapamycin-inhibits-ox-ldl-induced-inflammation-in-human-endothelial-cells-in-vitro-by-inhibiting-the-mtorc2-pkc-c-fos-pathway
#13
Juan-Juan Sun, Xiao-Wei Yin, Hui-Hui Liu, Wen-Xiu Du, Lu-Yao Shi, Ya-Bo Huang, Fen Wang, Chun-Feng Liu, Yong-Jun Cao, Yan-Lin Zhang
Rapamycin and its derivative possess anti-atherosclerosis activity, but its effects on adhesion molecule expression and macrophage adhesion to endothelial cells during atherosclerosis remain unclear. In this study we explored the effects of rapamycin on ox-LDL-induced adhesion molecule expression and macrophage adhesion to endothelial cells in vitro and the underlying mechanisms. Ox-LDL (6-48 μg/mL) dose-dependently increased the protein levels of two adhesion molecules, intercellular adhesion molecule-1 (ICAM-1) and E-selectin, in human umbilical vein endothelial cells (HUVECs), whereas pretreatment with rapamycin (1-10 μmol/L) dose-dependently inhibited ox-LDL-induced increase in the adhesion molecule expression and macrophage adhesion to endothelial cells...
October 26, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29070461/-rictor-mtorc2-regulates-blood-testis-barrier-and-spermatogenesis-in-mice
#14
He-Ling Dong, Hong-Yuan Wu, You Fu, Meng Dai, Xiao-Chun Bai, Hong Wang
OBJECTIVE: To investigate the role of Rictor/mTORC2 in the formation of blood testis barrier (BTB), testicular development, and spermatogenesis. METHODS: Amh Cre positive mice homozygous for rictor loxP with Sertoli cell specific deletion of rictor were obtained by cross breeding Amh Cre mice with rictor loxP mice. The histology of the reproductive organs, seminiferous tubules and epididymis of the transgenic mice was observed with HE staining. The cell subgroups of the germ cells in the seminiferous tubule were detected by flow cytometry with propidium iodide labeling...
October 20, 2017: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
https://www.readbyqxmd.com/read/29059166/mtorc2-akt-hsf1-hur-constitute-a-feed-forward-loop-regulating-rictor-expression-and-tumor-growth-in-glioblastoma
#15
B Holmes, A Benavides-Serrato, R S Freeman, K A Landon, T Bashir, R N Nishimura, J Gera
Overexpression of Rictor has been demonstrated to result in increased mechanistic target of rapamycin C2 (mTORC2) nucleation and activity leading to tumor growth and increased invasive characteristics in glioblastoma multiforme (GBM). However, the mechanisms regulating Rictor expression in these tumors is not clearly understood. In this report, we demonstrate that Rictor is regulated at the level of mRNA translation via heat-shock transcription factor 1 (HSF1)-induced HuR activity. HuR is shown to directly bind the 3' untranslated region of the Rictor transcript and enhance translational efficiency...
October 23, 2017: Oncogene
https://www.readbyqxmd.com/read/29051320/combinatorial-treatment-with-mtor-inhibitors-and-streptozotocin-leads-to-synergistic-in-vitro-and-in-vivo-antitumor-effects-in-insulinoma-cells
#16
Julien Bollard, Céline Patte, Patrick Massoma, Isabelle Goddard, Nicolas Gadot, Noura Benslama, Valérie Hervieu, Carole Ferraro-Peyret, Martine Cordier-Bussat, Jean-Yves Scoazec, Colette Roche, Thomas Walter, Cécile Vercherat
Streptozotocin (STZ)-based chemotherapy is the first-line chemotherapy recommended for advanced pancreatic neuroendocrine tumors (pNETs), while targeted therapies, including mTOR inhibitors, are available in second-line treatment. Unfortunately objective response rates to both treatments are limited. Since mTOR pathway activation, commonly observed in pNETs, has been reported as one of the major mechanisms accounting for chemoresistance, we investigated the potential benefit of mTOR inhibition combined with STZ treatment in a subset of pNETs, namely insulinomas...
October 19, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29051140/fgd5-faciogenital-dysplasia-5-regulates-vegf-vascular-endothelial-growth-factor-a-receptor-2-coupling-to-pi3-phosphoinositide-3-kinase-and-receptor-recycling
#17
Maikel A Farhan, Abul K Azad, Nicolas Touret, Allan G Murray
OBJECTIVE: VEGF (vascular endothelial growth factor-A) signaling to the endothelial cell (EC) through VEGFR2 (VEGF receptor-2) is the principal cue driving new blood vessel formation. FGD5 (faciogenital dysplasia-5)-a Rho-family guanine nucleotide exchange factor-is selectively expressed in EC. Deficiency of FGD5 is embryonically lethal in mice and perturbs angiogenesis and VEGF signal transduction. However, the mechanism of FGD5 regulation of VEGF signaling is poorly understood. APPROACH AND RESULTS: Angiogenic sprouting and EC cytoskeletal remodeling were evaluated in a 3-dimensional (3D) in vitro model...
October 19, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28993481/mtor-bach2-cascade-controls-cell-cycle-and-class-switch-recombination-during-b-cell-differentiation
#18
Toru Tamahara, Kyoko Ochiai, Akihiko Muto, Yukinari Kato, Nicolas Sax, Mitsuyo Matsumoto, Takeyoshi Koseki, Kazuhiko Igarashi
The transcription factor Bach2 regulates both acquired and innate immunity at multiple steps including antibody class switching and regulatory T cell development in activated B and T cells, respectively. However, little is known about the molecular mechanisms of Bach2 regulation in response to signaling of cytokines and antigen. We show here that mammalian target of rapamycin (mTOR) controls Bach2 along B cell differentiation with two distinct mechanisms in pre-B cells. Firstly, mTOR complex 1 (mTORC1) inhibited accumulation of Bach2 protein in nuclei and reduced its stability...
October 9, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28986255/down-regulation-of-peroxiredoxin-3-in-3t3-l1-adipocytes-leads-to-oxidation-of-rictor-in-the-mammalian-target-of-rapamycin-complex-2-mtorc2
#19
Dalay H Olson, Joel S Burrill, Jovan Kuzmicic, Wendy S Hahn, Ji-Man Park, Do-Hyung Kim, David A Bernlohr
Mitochondrially-derived oxidative stress has been implicated in the development of obesity-induced insulin resistance and is correlated with down regulation of Peroxiredoxin-3 (Prdx3). Prdx3 knockout mice exhibit whole-body insulin resistance, while Prdx3 transgenic animals remain insulin sensitive when placed on a high fat diet. To define the molecular events linking mitochondrial oxidative stress to insulin action, Prdx3 was silenced in 3T3-L1 adipocytes (Prdx3 KD) and the resultant cells evaluated for mitochondrial function, endoplasmic reticulum stress (ER stress), mitochondrial unfolded protein response (mtUPR) and insulin signaling...
November 25, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28979705/targeting-mtorc2-component-rictor-inhibits-cell-proliferation-and-promotes-apoptosis-in-gastric-cancer
#20
Yu-Hai Bian, Jia Xu, Wen-Yi Zhao, Zi-Zhen Zhang, Lin Tu, Hui Cao, Zhi-Gang Zhang
The mammalian target of rapamycin (mTOR) kinase acts downstream of phosphoinositide 3-kinase/Akt and plays an important role in tumor growth and progression of gastric cancer. It is well characterized that mTOR complex1 (mTORC1) controls cell metabolism and proliferation, whereas the contribution of mTOR complex2 (mTORC2) and its key component, Rictor, remains poorly understood. Therefore, we investigated clinical significance of Rictor expression by immunohistochemical analysis of 391 tissue samples from gastric cancer patients...
2017: American Journal of Translational Research
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