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https://www.readbyqxmd.com/read/28445935/inhibition-of-mtorc2-component-rictor-impairs-tumor-growth-in-pancreatic-cancer-models
#1
Katharina M Schmidt, Claus Hellerbrand, Petra Ruemmele, Christoph W Michalski, Bo Kong, Alexander Kroemer, Christina Hackl, Hans J Schlitt, Edward K Geissler, Sven A Lang
Mammalian Target of Rapamycin complex 2 (mTORC2) and its regulatory component Rapamycin-insensitive companion of mTOR (RICTOR) are increasingly recognized as important players in human cancer development and progression. However, the role of RICTOR in human pancreatic ductal adenocarcinoma (PDAC) is unclear so far. Here, we sought to analyze the effects of RICTOR inhibition in human pancreatic cancer cell lines in vitro and in vivo. Furthermore, RICTOR expression was determined in human PDAC samples. Results demonstrate that depletion of RICTOR with siRNA (transient knock-down) or shRNA (stable knock-down) has an inhibitory effect on tumor growth in vitro...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28435021/the-mtorc2-pkc-pathway-sustains-compensatory-insulin-secretion-of-pancreatic-%C3%AE-cells-in-response-to-metabolic-stress
#2
Yun Xie, Canqi Cui, Aifang Nie, Yan Wang, Qicheng Ni, Yun Liu, Qinglei Yin, Hongli Zhang, Yong Li, Qidi Wang, Yanyun Gu, Guang Ning
BACKGROUND: Compensation of the pancreatic β cell functional mass in response to metabolic stress is key to the pathogenesis of Type 2 Diabetes. The mTORC2 pathway governs fuel metabolism and β cell functional mass. It is unknown whether mTORC2 is required for regulating metabolic stress-induced β cell compensation. METHODS: We challenged four-week-old β-cell-specific Rictor (a key component of mTORC2)-knockout mice with a high fat diet (HFD) for 4weeks and measured metabolic and pancreatic morphological parameters...
April 20, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28410220/reprogramming-induced-by-isoliquiritigenin-diminishes-melanoma-cachexia-through-mtorc2-akt-gsk3%C3%AE-signaling
#3
Xiao-Yu Chen, De-Fang Li, Ji-Chun Han, Bo Wang, Zheng-Ping Dong, Li-Na Yu, Zhao-Hai Pan, Chuan-Jun Qu, Ying Chen, Shi-Guo Sun, Qiu-Sheng Zheng
Isoliquiritigenin (ISL), a member of the flavonoids, is known to have anti-tumor activity in vitro and in vivo. The effect of ISL on reprogramming in cancer cells, however, remains elusive. In this study, we investigated the effect of ISL on reprogramming in human melanoma A375 cells. ISL (15 μg/ml) significantly inhibited A375 cell proliferation, anchorage independent cell proliferation and G2/M cell cycle arrest after ISL exposure for 24 h. However, there were no significant changes in apoptosis rate. Terminal differentiation indicators (melanin content, melanogenesis mRNA expression, tyrosinase (TYR) activity) were all up-regulated by ISL treatment...
March 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28353644/methylmercury-induced-neurotoxicity-and-the-influence-of-selenium-in-the-brains-of-adult-zebrafish-danio-rerio
#4
Josef Daniel Rasinger, Anne-Katrine Lundebye, Samuel James Penglase, Ståle Ellingsen, Heidi Amlund
The neurotoxicity of methylmercury (MeHg) is well characterised, and the ameliorating effects of selenium have been described. However, little is known about the molecular mechanisms behind this contaminant-nutrient interaction. We investigated the influence of selenium (as selenomethionine, SeMet) and MeHg on mercury accumulation and protein expression in the brain of adult zebrafish (Danio rerio). Fish were fed diets containing elevated levels of MeHg and/or SeMet in a 2 × 2 full factorial design for eight weeks...
March 29, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28319045/akt-mediated-stabilization-of-histone-methyltransferase-whsc1-promotes-prostate-cancer-metastasis
#5
Ni Li, Wei Xue, Huairui Yuan, Baijun Dong, Yufeng Ding, Yongfeng Liu, Min Jiang, Shan Kan, Tongyu Sun, Jiale Ren, Qiang Pan, Xiang Li, Peiyuan Zhang, Guohong Hu, Yan Wang, Xiaoming Wang, Qintong Li, Jun Qin
Loss of phosphatase and tensin homolog (PTEN) and activation of the PI3K/AKT signaling pathway are hallmarks of prostate cancer (PCa). However, these alterations alone are insufficient for cells to acquire metastatic traits. Here, we have shown that the histone dimethyl transferase WHSC1 critically drives indolent PTEN-null tumors to become metastatic PCa. In a PTEN-null murine PCa model, WHSC1 overexpression in prostate epithelium cooperated with Pten deletion to produce a metastasis-prone tumor. Conversely, genetic ablation of Whsc1 prevented tumor progression in PTEN-null mice...
April 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28303961/the-metabolic-waste-ammonium-regulates-mtorc2-and-mtorc1-signaling
#6
Ahmad Merhi, Paul Delrée, Anna Maria Marini
Two structurally and functionally distinct mammalian TOR complexes control cell growth and metabolism in physiological and pathological contexts including cancer. Upregulated glutaminolysis is part of the metabolic reprogramming occurring in cancer, providing fuels for growth but also liberating ammonium, a potent neurotoxic waste product. Here, we identify ammonium as a novel dose-dependent signal mediating rapid mTORC2 activation and further regulating mTORC1. We show that ammonium induces rapid RICTOR-dependent phosphorylation of AKT-S473, a process requiring the PI3K pathway and further involving the Src-family kinase YES1, the FAK kinase and the ITGβ1 integrin...
March 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28300280/rapamycin-attenuates-baff-extended-proliferation-and-survival-via-disruption-of-mtorc1-2-signaling-in-normal-and-neoplastic-b-lymphoid-cells
#7
Qingyu Zeng, Shanshan Qin, Hai Zhang, Beibei Liu, Jiamin Qin, Xiaoxue Wang, Ruijie Zhang, Chunxiao Liu, Xiaoqing Dong, Shuangquan Zhang, Shile Huang, Long Chen
B cell activating factor from the TNF family (BAFF) stimulates B-cell proliferation and survival, but excessive BAFF promotes the development of aggressive B cells leading to malignant and autoimmune diseases. Recently, we have reported that rapamycin, a macrocyclic lactone, attenuates human soluble BAFF (hsBAFF)-stimulated B-cell proliferation/survival by suppressing mTOR-mediated PP2A-Erk1/2 signaling pathway. Here, we show that the inhibitory effect of rapamycin on hsBAFF-promoted B cell proliferation/survival is also related to blocking hsBAFF-stimulated phosphorylation of Akt, S6K1 and 4E-BP1, as well as expression of survivin in normal and B-lymphoid (Raji and Daudi) cells...
March 16, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28295259/applying-the-tor-c-que-in-inkt-cells-a-new-twist-in-an-old-tale
#8
Mihalis Verykokakis, Barbara L Kee
The mammalian Target of Rapamycin (mTOR) protein controls the machinery necessary for T-cell activation, differentiation, and memory formation, as a component of mTOR complex 1 (mTORC1) and mTORC2, which function both downstream and upstream of AKT. Invariant natural killer T (iNKT) cells are a unique T-cell subset that exist in a primed state, capable of rapid activation, and produce large quantities of cytokines. iNKT-cell effector differentiation is dependent on the mTORC1 complex; however, the requirements for mTORC2 in iNKT cells have been controversial...
March 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28294596/the-macrolide-toxin-mycolactone-promotes-bim-dependent-apoptosis-in-buruli-ulcer-through-inhibition-of-mtor
#9
Raphael Bieri, Nicole Scherr, Marie-Thérèse Ruf, Jean-Pierre Dangy, Philipp Gersbach, Matthias Gehringer, Karl-Heinz Altmann, Gerd Pluschke
Mycolactone, the macrolide exotoxin produced by Mycobacterium ulcerans, is central to the pathogenesis of the chronic necrotizing skin disease Buruli ulcer (BU). Here we show that mycolactone acts as an inhibitor of the mechanistic Target of Rapamycin (mTOR) signaling pathway by interfering with the assembly of the two distinct mTOR protein complexes mTORC1 and mTORC2, which regulate different cellular processes. Inhibition of the assembly of the rictor containing mTORC2 complex by mycolactone prevents phosphorylation of the serine/threonine protein kinase Akt...
March 27, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28288859/mitochondrial-toxicity-of-perfluorooctane-sulfonate-in-mouse-embryonic-stem-cell-derived-cardiomyocytes
#10
Lei-Lei Tang, Jia-Dan Wang, Ting-Ting Xu, Zhe Zhao, Jia-Jie Zheng, Ren-Shan Ge, Dan-Yan Zhu
Perfluorooctane sulfonate (PFOS) is a persistent organic contaminant that may cause cardiotoxicity in animals and humans. However, little is known about the underlying mechanism by which it affects the organelle toxicity in cardiomyocytes during the cardiogenesis. Our previous proteomic study showed that differences of protein expression mainly existed in mitochondria of cardiomyocytes differentiated from embryonic stem (ES) cells after exposure to PFOS. Here, we focused on mitochondrial toxicity of PFOS in ES cell-derived cardiomyocytes...
March 10, 2017: Toxicology
https://www.readbyqxmd.com/read/28287249/mtorc1-and-mtorc2-play-different-roles-in-regulating-cardiomyocyte-differentiation-from-embryonic-stem-cells
#11
Bei Zheng, Jiadan Wang, Leilei Tang, Jiana Shi, Danyan Zhu
Mammalian target of rapamycin (mTOR) is a serine/threonine kinase and functions through two distinct complexes, mTOR complex 1 (mTORC1) and complex 2 (mTORC2), with their key components Raptor and Rictor, to play crucial roles in cellular survival and growth. However, the roles of mTORC1 and mTORC2 in regulating cardiomyocyte differentiation from mouse embryonic stem (mES) cells are not clear. In this study, we performed Raptor or Rictor knockdown experiments to investigate the roles of mTORC1 and mTORC2 in cardiomyocyte differentiation...
2017: International Journal of Developmental Biology
https://www.readbyqxmd.com/read/28278709/microrna-185-5p-restores-glucocorticoid-sensitivity-by-suppressing-the-mammalian-target-of-rapamycin-complex-mtorc-signaling-pathway-to-enhance-glucocorticoid-receptor-autoregulation
#12
Peisong Chen, Ting Shen, Huimin Wang, Zhiyong Ke, Yaru Liang, Juan Ouyang, Tang Jiang
Overexpression of microRNA-185-5p (miR-185-5p) in glucocorticoid (GC)-sensitive acute lymphoblastic leukemia (ALL) was identified using a microarray and reverse transcription polymerase chain reaction and was further confirmed in ALL cell lines. A reporter assay confirmed that the Rictor-one component of mammalian target of rapamycin complex 2 (mTORC2) is a target of miR-185-5p. Decreased mTORC activity was also confirmed in GC-sensitive patients. Overexpression of miR-185-5p significantly enhanced GC sensitivity in CEM-C1 cells (GC resistance) by increasing the rate of cell apoptosis and cycle arrest, and decreasing cell survival, accompanied by a decrease in mTORC activity and an increase in GC-induced glucocorticoid receptor (GR) expression...
February 28, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28273354/mtorc2-controls-th9-polarization-and-allergic-airway-inflammation
#13
H Chen, L Zhang, P Wang, H Su, W Wang, Z Chu, L Zhang, X Zhang, Y Zhao
BACKGROUND: T helper type 9 (Th9) cells, a subpopulation of CD4(+) T cells, play a critical role in the pathogenesis of allergic airway inflammation. However, it remains unknown whether mTORC2 regulates Th9 differentiation or function during allergic inflammation. METHODS: T-cell-specific Rictor-deficient mice, a mouse model of allergic airway inflammation induced by ovalbumin (OVA) sensitization and a mouse model of adoptive transfer of induced Th9 cells, were used to address the roles of mTORC2 in the pathogenesis of allergic airway inflammation...
March 8, 2017: Allergy
https://www.readbyqxmd.com/read/28240051/microrna-185-induces-potent-autophagy-via-akt-signaling-in-hepatocellular-carcinoma
#14
Li Zhou, Shunai Liu, Ming Han, Shenghu Feng, Jinqiu Liang, Zhongshu Li, Yaru Li, Hongping Lu, Ting Liu, Yanhua Ma, Jun Cheng
Studies have demonstrated that microRNA 185 may be a promising therapeutic target in liver cancer. However, its role in hepatocellular carcinoma is largely unknown. In this study, the proliferation of human HepG2 cells was inhibited by transfection of microRNA 185 mimics. Cell-cycle analysis revealed arrest at the G0/G1 phase. Transfection of HepG2 cells with microRNA 185 mimics significantly induced apoptosis. These data confirmed microRNA 185 as a potent cancer suppressor. We demonstrated that microRNA 185 was a compelling inducer of autophagy, for the first time...
February 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28211872/rictor-mtorc2-deficiency-enhances-keratinocyte-stress-tolerance-via-mitohormesis
#15
Beatrice Tassone, Stefania Saoncella, Francesco Neri, Ugo Ala, Davide Brusa, Mark A Magnuson, Paolo Provero, Salvatore Oliviero, Chiara Riganti, Enzo Calautti
How metabolic pathways required for epidermal tissue growth and remodeling influence the ability of keratinocytes to survive stressful conditions is still largely unknown. The mechanistic target of rapamycin complex 2 (mTORC2) regulates growth and metabolism of several tissues, but its functions in epidermal cells are poorly defined. Rictor is an adaptor protein essential for mTORC2 activity. To explore the roles of mTORC2 in the epidermis, we have conditionally deleted rictor in mice via K14-Cre-mediated homologous recombination and found that its deficiency causes moderate tissue hypoplasia, reduced keratinocyte proliferation and attenuated hyperplastic response to TPA...
April 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28167137/deletion-of-rictor-in-catecholaminergic-neurons-alters-locomotor-activity-and-ingestive-behavior
#16
Sophia Kaska, Rebecca Brunk, Vedrana Bali, Megan Kechner, Michelle S Mazei-Robison
While the etiology of depression is not fully understood, increasing evidence from animal models suggests a role for the ventral tegmental area (VTA) in pathogenesis. In this paper, we investigate the potential role of VTA mechanistic target of rapamycin 2 (TORC2) signaling in mediating susceptibility to chronic social defeat stress (CSDS), a well-established mouse model of depression. Utilizing genetic and viral knockout of Rictor (rapamycin-insensitive companion of target of rapamycin), a requisite component of TORC2, we demonstrate that decreasing Rictor-dependent TORC2 signaling in catecholaminergic neurons, or within the VTA specifically, does not alter susceptibility to CSDS...
May 1, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28134789/mrpl10-and-tbp-are-suitable-reference-genes-for-peripheral-nerve-crush-injury
#17
Yaxian Wang, Qianqian Shan, Yali Meng, Jiacheng Pan, Sheng Yi
Peripheral nerve injury triggers the dysregulation of a large number of genes at multiple sites, including neurons, peripheral nerve stump, and the target organ. Housekeeping genes were frequently used as reference genes to normalize the expression values of target genes. Suitable selection of housekeeping genes that are stably expressed after nerve injury minimizes bias elicited by reference genes and thus helps to better and more sensitively reflect gene expression changes. However, many housekeeping genes have been used as reference genes without testing the expression patterns of themselves...
January 27, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28132115/rictor-expression-in-esophageal-squamous-cell-carcinoma-and-its-clinical-significance
#18
Wei-Jia Jiang, Ru-Xue Feng, Jia-Tao Liu, Lu-Lu Fan, Hua Wang, Guo-Ping Sun
Esophageal cancer is one of the most common malignant tumors in the world, and its incidence is the eighth highest; meanwhile, its fatality rate is the sixth highest. The PI3K/Akt/mTOR signaling pathway plays a required role in human cancer, including cell survival, metabolism and migration. As a kind of important scaffold protein in mTORC2, RICTOR has showed over-expression in several malignancies like melanoma and endometrial cancer. In this research, we selected 201 cases of paraffin specimens from patients diagnosed as esophageal squamous cell carcinoma after surgical treatment and then estimated the RICTOR expression in each esophageal squamous cell carcinoma tissue by using the immunohistochemical streptavidin-peroxidase technique...
March 2017: Medical Oncology
https://www.readbyqxmd.com/read/28128208/mtorc2-signalling-regulates-m2-macrophage-differentiation-in-response-to-helminth-infection-and-adaptive-thermogenesis
#19
R W Hallowell, S L Collins, J M Craig, Y Zhang, M Oh, P B Illei, Y Chan-Li, C L Vigeland, W Mitzner, A L Scott, J D Powell, M R Horton
Alternatively activated macrophages (M2) have an important function in innate immune responses to parasitic helminths, and emerging evidence also indicates these cells are regulators of systemic metabolism. Here we show a critical role for mTORC2 signalling in the generation of M2 macrophages. Abrogation of mTORC2 signalling in macrophages by selective conditional deletion of the adaptor molecule Rictor inhibits the generation of M2 macrophages while leaving the generation of classically activated macrophages (M1) intact...
January 27, 2017: Nature Communications
https://www.readbyqxmd.com/read/28123351/involvement-of-rictor-mtorc2-in-cardiomyocyte-differentiation-of-mouse-embryonic-stem-cells-in-vitro
#20
Bei Zheng, Jiadan Wang, Leilei Tang, Chao Tan, Zhe Zhao, Yi Xiao, Renshan Ge, Danyan Zhu
Rictor is a key regulatory/structural subunit of the mammalian target of rapamycin complex 2 (mTORC2) and is required for phosphorylation of Akt at serine 473. It plays an important role in cell survival, actin cytoskeleton organization and other processes in embryogenesis. However, the role of Rictor/mTORC2 in the embryonic cardiac differentiation has been uncovered. In the present study, we examined a possible link between Rictor expression and cardiomyocyte differentiation of the mouse embryonic stem (mES) cells...
2017: International Journal of Biological Sciences
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