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mtorc2 inhibitor

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https://www.readbyqxmd.com/read/28993481/mtor-bach2-cascade-controls-cell-cycle-and-class-switch-recombination-during-b-cell-differentiation
#1
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/28979705/targeting-mtorc2-component-rictor-inhibits-cell-proliferation-and-promotes-apoptosis-in-gastric-cancer
#2
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
https://www.readbyqxmd.com/read/28968999/association-of-msin1-with-mtorc2-ras-and-akt-reveals-a-crucial-domain-on-msin1-involved-in-akt-phosphorylation
#3
Chien-An Yao, Sara Ortiz-Vega, Yun-Ya Sun, Chiang-Ting Chien, Jen-Hua Chuang, Yenshou Lin
mSin1 is a unique component within the mammalian target of rapamycin (mTOR) complex 2 (mTORC2), which is responsible for cellular morphology and glucose metabolism. The association between mSin1 and other mTORC2 components, as well as their functions, has been explored previously; nevertheless, the mapping of the various binding domains of the components is lacking. Based on an evolutionary analysis of the gene, we constructed various fragments and truncated-forms of mSin1. We characterized the individual binding sites of mSin1 with its various partners, including mTOR, Rictor, Ras, and Akt...
September 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28967097/chronic-treatment-with-novel-nanoformulated-micelles-of-rapamycin-rapatar-protects-diabetic-heart-against-ischemia-reperfusion-injury
#4
Arun Samidurai, Fadi N Salloum, David Durrant, Olga B Chernova, Rakesh C Kukreja, Anindita Das
BACKGROUND: Enhanced mammalian target of rapamycin (mTOR) signaling contributes to the pathogenesis of diabetes and plays a critical role in myocardial ischemia/reperfusion (I/R) injury. Rapatar is a novel nanoformulated micellar of rapamycin, a putative inhibitor of mTOR, that have been rationally designed to increase water solubility of rapamycin in order to facilitate oral administration and enhance bioavailability. We examined the effect of Rapatar in improving metabolic status and protection against myocardial I/R injury in type 2 diabetic (T2D) mice...
October 1, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28953980/influenza-virus-differentially-activates-mtorc1-and-mtorc2-signaling-to-maximize-late-stage-replication
#5
Sharon K Kuss-Duerkop, Juan Wang, Ignacio Mena, Kris White, Giorgi Metreveli, Ramanavelan Sakthivel, Miguel A Mata, Raquel Muñoz-Moreno, Xiang Chen, Florian Krammer, Michael S Diamond, Zhijian J Chen, Adolfo García-Sastre, Beatriz M A Fontoura
Influenza A virus usurps host signaling factors to regulate its replication. One example is mTOR, a cellular regulator of protein synthesis, growth and motility. While the role of mTORC1 in viral infection has been studied, the mechanisms that induce mTORC1 activation and the substrates regulated by mTORC1 during influenza virus infection have not been established. In addition, the role of mTORC2 during influenza virus infection remains unknown. Here we show that mTORC2 and PDPK1 differentially phosphorylate AKT upon influenza virus infection...
September 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28938571/preclinical-study-of-cc223-as-a-potential-anti-ovarian-cancer-agent
#6
Zhenzhen Jin, Huanfu Niu, Xuenan Wang, Lei Zhang, Qin Wang, Aijun Yang
Aberrant activation of mTOR contributes to ovarian cancer progression. CC223 is a novel and potent mTOR kinase inhibitor. The current study tested its activity against human ovarian cancer cells. We showed that CC223, at nM concentrations, inhibited survival and proliferation of established/primary human ovarian cancer cells. Further, significant apoptosis activation was observed in CC223-treated ovarian cancer cells. CC223 disrupted assembly of mTOR complex 1 (mTORC1) and mTORC2 in SKOV3 cells. Meanwhile, activation of mTORC1 and mTORC2 was almost completely blocked by CC223...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28916818/identification-of-4-phenylquinolin-2-1h-one-as-a-specific-allosteric-inhibitor-of-akt
#7
Bill X Huang, Kenny Newcomer, Karl Kevala, Elena Barnaeva, Wei Zheng, Xin Hu, Samarjit Patnaik, Noel Southall, Juan Marugan, Marc Ferrer, Hee-Yong Kim
Akt plays a major role in tumorigenesis and the development of specific Akt inhibitors as effective cancer therapeutics has been challenging. Here, we report the identification of a highly specific allosteric inhibitor of Akt through a FRET-based high-throughput screening, and characterization of its inhibitory mechanism. Out of 373,868 compounds screened, 4-phenylquinolin-2(1H)-one specifically decreased Akt phosphorylation at both T308 and S473, and inhibited Akt kinase activity (IC50 = 6 µM) and downstream signaling...
September 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28916338/structure-activity-relationship-study-of-small-molecule-inhibitors-of-the-deptor-mtor-interaction
#8
Jihye Lee, Yijiang Shi, Mario Vega, Yonghui Yang, Joseph Gera, Michael E Jung, Alan Lichtenstein
DEPTOR is a 48kDa protein that binds to mTOR and inhibits this kinase within mTORC1 and mTORC2 complexes. Over-expression of DEPTOR specifically occurs in the multiple myeloma (MM) tumor model and DEPTOR knockdown is cytotoxic to MM cells, suggesting it is a potential therapeutic target. Since mTORC1 paralysis protects MM cells against DEPTOR knockdown, it indicates that the protein-protein interaction between DEPTOR and mTOR is key to MM viability vs death. In a previous study, we used a yeast two-hybrid screen of a small inhibitor library to identify a compound that inhibited DEPTOR/mTOR binding in yeast...
September 6, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28888905/selective-interference-of-mtorc1-raptor-protects-against-human-disc-cellular-apoptosis-senescence-and-extracellular-matrix-catabolism-with-akt-and-autophagy-induction
#9
M Ito, T Yurube, K Kakutani, K Maeno, T Takada, Y Terashima, Y Kakiuchi, Y Takeoka, S Miyazaki, R Kuroda, K Nishida
OBJECTIVE: The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that integrates nutrients to execute cell growth and protein synthesis. We hypothesized that mTOR is essential for the intervertebral disc, the largest avascular, low-nutrient organ. Our objective was to elucidate roles of mTOR signaling in human disc cells. DESIGN: The mTOR exists in two complexes: mTORC1 containing the regulatory-associated protein of mTOR (RAPTOR) and mTORC2 containing the rapamycin-insensitive companion of mTOR (RICTOR)...
September 6, 2017: Osteoarthritis and Cartilage
https://www.readbyqxmd.com/read/28885497/influence-of-the-novel-atp-competitive-dual-mtorc1-2-inhibitor-azd2014-on-immune-cell-populations-and-heart-allograft-rejection
#10
Daniel Fantus, Helong Dai, Yoshihiro Ono, Alicia Watson, Shinichiro Yokota, Kanishka Mohib, Osamu Yoshida, Mark A Ross, Simon C Watkins, Bala Ramaswami, Anna Valusjkikh, David M Rothstein, Angus W Thomson
BACKGROUND: Little is known about how new generation adenosine triphosphate (ATP)-competitive mechanistic target of rapamycin (mTOR) kinase inhibitors (TORKinibs) affect immunity and allograft rejection. METHODS: mTOR complex (C) 1 and 2 signaling in dendritic cells (DC) and T cells was analyzed by Western blotting, while immune cell populations in normal and heart allograft recipient mice were analyzed by flow cytometry. Alloreactive T cell proliferation was quantified in MLR; intracellular cytokine production and serum antidonor IgG levels were determined by flow analysis and immunofluorescence staining used to detect IgG in allografts...
September 6, 2017: Transplantation
https://www.readbyqxmd.com/read/28819418/cenph-inhibits-rapamycin-sensitivity-by-regulating-golph3-dependent-mtor-signaling-pathway-in-colorectal-cancer
#11
Wei Wu, Fan Wu, Zaozao Wang, Jiabo Di, Jie Yang, Pin Gao, Beihai Jiang, Xiangqian Su
Background: Centromere protein H (CENPH) is known as a fundamental component of the active centromere complex, and its overexpression is correlated with poor prognosis in various solid tumors. mTOR inhibitor rapamycin has been shown to possess antitumor activity, as well as prevent intestinal tumorigenesis. However, the prognostic value of CENPH in colorectal cancer (CRC) and the role of CENPH in rapamycin sensitivity remain unknown. Materials and methods: The effect of CENPH on the cell proliferation, clonogenicity, and cell response to rapamycin in CRC were evaluated by MTT and/or colony formation assays...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28761330/epigenetic-memory-of-oxidative-stress-does-nephrilin-exert-its-protective-effects-via-rac1
#12
Desmond D Mascarenhas, David N Herndon, Istvan Arany
AIM: Nephrilin peptide, a designed inhibitor of Rictor complex (mTORC2), exerts pleiotropic protective effects in metabolic, xenobiotic and traumatic stress models. Stress can generate enduring epigenetic changes in gene function. In this work we examine the possibility that nephrilin treatment protects against acute and enduring global changes in oxidative metabolism, with a focus on the Rictor-complex-mediated activation of Rac1, a subunit of NADPH oxidase (Nox) via PKCs, Prex1 and p66shc...
2017: Biologics: Targets & Therapy
https://www.readbyqxmd.com/read/28733220/pan-mtor-inhibitor-mln0128-is-effective-against-intrahepatic-cholangiocarcinoma-induced-in-mice-by-akt-and-yap-co-expression
#13
Shanshan Zhang, Xinhua Song, Dan Cao, Zhong Xu, Biao Fan, Li Che, Junjie Hu, Bin Chen, Mingjie Dong, Maria G Pilo, Antonio Cigliano, Katja Evert, Silvia Ribback, Frank Dombrowski, Rosa M Pascale, Antonio Cossu, Gianpaolo Vidili, Alberto Porcu, Maria M Simile, Giovanni M Pes, Gianluigi Giannelli, John Gordan, Lixin Wei, Matthias Evert, Wenming Cong, Diego F Calvisi, Xin Chen
BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (ICC) is a lethal malignancy without effective treatment options. MLN0128, a second-generation pan-mTOR inhibitor, shows efficacy for multiple tumor types. METHODS: We established a novel ICC mouse model via hydrodynamic transfection of activated forms of AKT (myr-AKT) and Yap (YapS127A) protooncogenes (that will be referred to as AKT/YapS127A). Genetic approaches were applied to study the requirement of mTORC1 and mTORC2 in mediating AKT/YapS127A driven tumorigenesis...
July 18, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28730764/mtor-deregulation-in-oral-cavity-squamous-cell-carcinoma
#14
Nicholas S Mastronikolis, Evangelos Tsiambas, Theodoros A Papadas, Panagiotis P Fotiades, Athanasios T Papadas, Stylianos N Mastronikolis, Ioannis Kastanioudakis, Vasileios Ragos
Signal transduction pathways consist of a variety of inter- and intra-cellular molecules. They act as supporting mechanisms for cell survival and homeostasis. Among them, the phosphatidylinositol 3-kinase (PI3K)/tumor suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway plays a crucial role in regulating normal cell growth based on growth factor receptors (GFRs) interaction, including epidermal GFR (type II-HER2) and insulin GFR (IGF)...
May 2017: Journal of B.U.ON.: Official Journal of the Balkan Union of Oncology
https://www.readbyqxmd.com/read/28711935/association-of-msin1-with-mtorc2-ras-and-akt-reveals-a-crucial-domain-on-msin1-involved-in-akt-phosphorylation
#15
Chien-An Yao, Sara Ortiz-Vega, Yun-Ya Sun, Chiang-Ting Chien, Jen-Hua Chuang, Yenshou Lin
mSin1 is a unique component within the mammalian target of rapamycin (mTOR) complex 2 (mTORC2), which is responsible for cellular morphology and glucose metabolism. The association between mSin1 and other mTORC2 components, as well as their functions, has been explored previously; nevertheless, the mapping of the various binding domains of the components is lacking. Based on an evolutionary analysis of the gene, we constructed various fragments and truncated-forms of mSin1. We characterized the individual binding sites of mSin1 with its various partners, including mTOR, Rictor, Ras, and Akt...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28703798/mtorc2-regulates-hedgehog-pathway-activity-by-promoting-stability-to-gli2-protein-and-its-nuclear-translocation
#16
Samarpan Maiti, Susmita Mondal, Eswara M Satyavarapu, Chitra Mandal
mTORC2 is aberrantly activated in cancer and therefore is considered to be an important therapeutic target. The hedgehog pathway, which is also often hyperactivated, regulates transcription of several genes associated with angiogenesis, metastasis, cellular proliferation and cancer stem cell (CSC) regeneration. However, the contribution of mTORC2 toward hedgehog pathway activity has not been explored yet. Here we have addressed the molecular cross talk between mTORC2 and hedgehog pathway activities in the context of glioblastoma multiforme, a malignant brain tumor using as a model system...
July 13, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28699701/rictor-regulates-the-vasculogenic-mimicry-of-melanoma-via-the-akt-mmp-2-9-pathway
#17
Xingmei Liang, Ran Sun, Xiulan Zhao, Yanhui Zhang, Qiang Gu, Xueyi Dong, Danfang Zhang, Junying Sun, Baocun Sun
Vasculogenic mimicry (VM)-positive melanomas are usually associated with poor prognosis. Rictor, the key component of the rapamycin-insensitive complex of mTOR (mTORC2), is up-regulated in several cancers, especially in melanomas with poor prognosis. The aim of this study was to investigate the role of Rictor in the regulation of VM and the mechanism underlying this possible regulation. VM channels were found in 35 of 81 tested melanoma samples and high Rictor expression correlated with VM structures. Moreover, Kaplan-Meier survival curves indicated that VM structures and high Rictor expression correlated with shorter survival in patients with melanoma...
July 12, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28679058/pharmacological-inhibition-of-mtor-kinase-reverses-right-ventricle-remodeling-and-improves-right-ventricle-structure-and-function-in-rats
#18
Andressa Pena, Ahasanul Kobir, Dmitry Goncharov, Akiko Goda, Tatiana V Kudryashova, Arnab Ray, Rebecca Vanderpool, Jeffrey Baust, Baojun Chang, Ana L Mora, John Gorcsan Iii, Elena A Goncharova
Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling, increased pulmonary artery pressure (PAP), right heart afterload and death. Mechanistic target of rapamycin (mTOR) promotes smooth muscle cell proliferation, survival and pulmonary vascular remodeling via two functionally distinct complexes, mTORC1 (supports cell growth) and mTORC2 (promotes cell survival), and dual mTORC1/mTORC2 inhibition selectively induces PAH PAVSMC apoptosis and reverses pulmonary vascular remodeling...
July 5, 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/28666462/two-distinct-mtorc2-dependent-pathways-converge-on-rac1-to-drive-breast-cancer-metastasis
#19
Meghan Morrison Joly, Michelle M Williams, Donna J Hicks, Bayley Jones, Violeta Sanchez, Christian D Young, Dos D Sarbassov, William J Muller, Dana Brantley-Sieders, Rebecca S Cook
BACKGROUND: The importance of the mTOR complex 2 (mTORC2) signaling complex in tumor progression is becoming increasingly recognized. HER2-amplified breast cancers use Rictor/mTORC2 signaling to drive tumor formation, tumor cell survival and resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapy. Cell motility, a key step in the metastatic process, can be activated by mTORC2 in luminal and triple negative breast cancer cell lines, but its role in promoting metastases from HER2-amplified breast cancers is not yet clear...
June 30, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/28611306/erk-inhibition-sensitizes-cz415-induced-anti-osteosarcoma-activity-in-vitro-and-in-vivo
#20
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...
May 30, 2017: Oncotarget
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