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mtorc2 inhibitor

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https://www.readbyqxmd.com/read/28819418/cenph-inhibits-rapamycin-sensitivity-by-regulating-golph3-dependent-mtor-signaling-pathway-in-colorectal-cancer
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
https://www.readbyqxmd.com/read/28602697/gsk3-inhibitor-ar-a014418-promotes-osteogenic-differentiation-of-human-adipose-derived-stem-cells-via-erk-and-mtorc2-akt-signaling-pathway
#11
Min Zhang, Ping Zhang, Yunsong Liu, Yongsheng Zhou
Small molecule-based bone tissue engineering is emerging as a promising strategy for bone defects restoration. In this study, we intended to identify the roles and mechanisms of AR-A014418, a highly selective inhibitor of GSK3, on the osteogenic differentiation. We found that AR-A014418 exhibited a dose-dependent effect on osteogenic differentiation of human adipose-derived stem cells (hASCs). hASCs treated with AR-A014418 showed higher activity of ERK and mTORC2/Akt signaling. Administration of ERK inhibitor U0126 or knockdown of RICTOR by siRNA attenuated AR-A014418 induced osteogenic differentiation of hASCs...
August 19, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28569556/guaran%C3%A3-a-highly-caffeinated-food-presents-in-vitro-antitumor-activity-in-colorectal-and-breast-cancer-cell-lines-by-inhibiting-akt-mtor-s6k-and-mapks-pathways
#12
Francine C Cadoná, Jose L Rosa, Taiane Schneider, Monica Cubillos-Rojas, Susana Sánchez-Tena, Verônica F Azzolin, Charles E Assmann, Alencar K Machado, Euler E Ribeiro, Ivana Beatrice M da Cruz
The mammalian target of rapamycin (mTOR) and mitogen-activated protein kinases (MAPKs) pathways are frequently upregulated in cancer. Some authors have reported that some antioxidant molecules could be potential inhibitors of these pathways. Therefore, we investigated the in vitro antitumor effect of guaraná by inhibiting the AKT/mTOR/S6K and MAPKs pathways. Colorectal and breast cancer cell lineages, HT-29 and MCF-7 cells, respectively, were exposed to different guaraná concentrations (0.1, 1, 10, and 100 µg/mL) as well as its main bioactive molecule, caffeine, in proportional concentrations to those found in the extract...
July 2017: Nutrition and Cancer
https://www.readbyqxmd.com/read/28566383/drug-modulators-of-b-cell-signaling-pathways-and-epstein-barr-virus-lytic-activation
#13
John G Kosowicz, Jaeyeun Lee, Brandon Peiffer, Zufeng Guo, Jianmeng Chen, Gangling Liao, S Diane Hayward, Jun O Liu, Richard F Ambinder
Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus that establishes a latency reservoir in B cells. In this work, we show that ibrutinib, idelalisib, and dasatinib, drugs that block B cell receptor (BCR) signaling and are used in the treatment of hematologic malignancies, block BCR-mediated lytic induction at clinically relevant doses. We confirm that the immunosuppressive drugs cyclosporine and tacrolimus also inhibit BCR-mediated lytic induction but find that rapamycin does not inhibit BCR-mediated lytic induction...
August 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28548926/preclinical-study-of-cc223-as-a-potential-anti-ovarian-cancer-agent
#14
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...
May 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28544747/k-ras-mutation-and-amplification-status-is-predictive-of-resistance-and-high-basal-pakt-is-predictive-of-sensitivity-to-everolimus-in-biliary-tract-cancer-cell-lines
#15
Yvonne Yeung, David K Lau, Fiona Chionh, Hoanh Tran, Janson W T Tse, Andrew J Weickhardt, Mehrdad Nikfarjam, Andrew M Scott, Niall C Tebbutt, John M Mariadason
Advanced biliary tract cancer (BTC) has a poor prognosis and limited treatment options. The PI3K/Akt/mTOR signaling pathway is hyperactivated in a subset of BTCs and clinical activity to the mTOR inhibitor everolimus has been observed in some BTC patients. The goal of this study was to identify biomarkers predictive of everolimus response. Twenty BTC cell lines were assessed for everolimus sensitivity with a spectrum of growth inhibitory responses observed. Molecular biomarkers of sensitivity and resistance were identified by interrogation of the activation status of the Ras/MAPK and PI3K/Akt/mTOR pathways...
May 24, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28453552/specific-blockade-of-rictor-mtor-association-inhibits-mtorc2-activity-and-is-cytotoxic-in-glioblastoma
#16
Angelica Benavides-Serrato, Jihye Lee, Brent Holmes, Kenna A Landon, Tariq Bashir, Michael E Jung, Alan Lichtenstein, Joseph Gera
A small molecule which specifically blocks the interaction of Rictor and mTOR was identified utilizing a high-throughput yeast two-hybrid screen and evaluated as a potential inhibitor of mTORC2 activity in glioblastoma multiforme (GBM). In vitro, CID613034 inhibited mTORC2 kinase activity at submicromolar concentrations and in cellular assays specifically inhibited phosphorylation of mTORC2 substrates, including AKT (Ser-473), NDRG1 (Thr-346) and PKCα (Ser-657), while having no appreciable effects on the phosphorylation status of the mTORC1 substrate S6K (Thr-389) or mTORC1-dependent negative feedback loops...
2017: PloS One
https://www.readbyqxmd.com/read/28434143/the-mtor-signaling-pathway-in-myocardial-dysfunction-in-type-2-diabetes-mellitus
#17
REVIEW
Tomohiro Suhara, Yuichi Baba, Briana K Shimada, Jason K Higa, Takashi Matsui
PURPOSE OF REVIEW: T2DM (type 2 diabetes mellitus) is a risk factor for heart failure. The mTOR (mechanistic target of rapamycin) is a key mediator of the insulin signaling pathway. We will discuss the role of mTOR in myocardial dysfunction in T2DM. RECENT FINDINGS: In T2DM, chronically activated mTOR induces multiple pathological events, including a negative feedback loop that suppresses IRS (insulin receptor substrate)-1. While short-term treatment with rapamycin, an mTOR inhibitor, is a promising strategy for cardiac diseases such as acute myocardial infarction and cardiac hypertrophy in T2DM, there are many concerns about chronic usage of rapamycin...
June 2017: Current Diabetes Reports
https://www.readbyqxmd.com/read/28410220/reprogramming-induced-by-isoliquiritigenin-diminishes-melanoma-cachexia-through-mtorc2-akt-gsk3%C3%AE-signaling
#18
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...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28404914/the-preclinical-assessment-of-xl388-a-mtor-kinase-inhibitor-as-a-promising-anti-renal-cell-carcinoma-agent
#19
Zuquan Xiong, Yiwen Zang, Shan Zhong, Lujia Zou, Yishuo Wu, Shenghua Liu, Zujun Fang, Zhoujun Shen, Qiang Ding, Shanwen Chen
XL388 is a mammalian target of rapamycin (mTOR) kinase inhibitor. We demonstrated that XL388 inhibited survival and proliferation of renal cell carcinoma (RCC) cell lines (786-0 and A549) and primary human RCC cells. XL388 activated caspase-dependent apoptosis in the RCC cells. XL388 blocked mTOR complex 1 (mTORC1) and mTORC2 activation, and depleted hypoxia-inducible factor 1α (HIF1α) and HIF-2α expression in RCC cells. Yet, XL388 was ineffective in RCC cells with mTOR shRNA knockdown or kinase-dead mutation...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28404689/methoxyluteolin-inhibits-neuropeptide-stimulated-proinflammatory-mediator-release-via-mtor-activation-from-human-mast-cells
#20
Arti B Patel, Theoharis C Theoharides
Mast cells (MCs) are critical for allergic reactions but are also important in inflammatory processes. Stimulation by neuropeptides, such as substance P (SP) and neurotensin (NT), leads to release of preformed molecules stored in numerous MC secretory granules and newly synthesized proinflammatory mediators, including tumor necrosis factor, C-X-C motif chemokine ligand 8, and vascular endothelial growth factor. Here, we investigate the role of mammalian target of rapamycin (mTOR) signaling in the stimulation of cultured human LAD2 MCs by NT or SP, as well as the inhibitory effect of the natural flavonoids 3',4',5,7-tetrahydroxyflavone (luteolin) and its novel structural analog 3',4',5,7-tetramethoxyflavone (methoxyluteolin)...
June 2017: Journal of Pharmacology and Experimental Therapeutics
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