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mtorc2 inhibitor

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https://www.readbyqxmd.com/read/27922192/evidence-for-pipecolate-oxidase-in-mediating-protection-against-hydrogen-peroxide-stress
#1
Sathish Kumar Natarajan, Ezhumalai Muthukrishnan, Oleh Khalimonchuk, Justin L Mott, Donald F Becker
Pipecolate, an intermediate of the lysine catabolic pathway, is oxidized to Δ(1) -piperideine-6-carboxylate (P6C) by the flavoenzyme L-pipecolate oxidase (PIPOX). P6C spontaneously hydrolyzes to generate α-aminoadipate semialdehyde, which is then converted into α-aminoadipate acid by α-aminoadipatesemialdehyde dehydrogenase. L-pipecolate was previously reported to protect mammalian cells against oxidative stress. Here, we examined whether PIPOX is involved in the mechanism of pipecolate stress protection...
December 6, 2016: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/27884298/mhy1485-activates-mtor-and-protects-osteoblasts-from-dexamethasone
#2
Sai Zhao, Caiyun Chen, Shouguo Wang, Feng Ji, Yue Xie
Dexamethasone (Dex) exerts cytotoxic effects to cultured osteoblasts. The potential effect of MHY1485, a small-molecular mammalian target of rapamycin (mTOR) activator, against the process was studied here. In both osteoblastic MC3T3-E1 cells and primary murine osteoblasts, treatment with MHY1485 significantly ameliorated Dex-induced cell death and apoptosis. mTOR inhibition, through mTOR kinase inhibitor OSI-027 or mTOR shRNAs, abolished MHY1485-mediated osteoblast cytoprotection against Dex. Intriguingly, activation of mTOR complex (mTORC1), but not mTORC2, is required for MHY1485's anti-Dex activity...
December 9, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27854154/small-gtpases-in-c-elegans-metabolism
#3
Daniel Z Bar, Chayki Charar, Yosef Gruenbaum
The mechanistic target of rapamycin (mTOR) is an evolutionary conserved protein with a serine/threonine kinase activity that regulates cell growth, proliferation, motility, survival, protein synthesis, autophagy and transcription. It is embedded in 2 large protein complexes: mTORC1 and mTORC2. Regulation of specific mTOR pathway functions depends on multiple GTPases, that act either as regulators of mTOR protein complexes, coupling energy availability with mTORC1 activity, or as downstream effectors of both mTORC1 and mTORC2...
November 17, 2016: Small GTPases
https://www.readbyqxmd.com/read/27826244/judicious-toggling-of-mtor-activity-to-combat-insulin-resistance-and-cancer-current-evidence-and-perspectives
#4
REVIEW
Pei Shi Ong, Louis Z Wang, Xiaoyun Dai, Sheng Hsuan Tseng, Shang Jun Loo, Gautam Sethi
The mechanistic target of rapamycin (mTOR), via its two distinct multiprotein complexes, mTORC1, and mTORC2, plays a central role in the regulation of cellular growth, metabolism, and migration. A dysregulation of the mTOR pathway has in turn been implicated in several pathological conditions including insulin resistance and cancer. Overactivation of mTORC1 and disruption of mTORC2 function have been reported to induce insulin resistance. On the other hand, aberrant mTORC1 and mTORC2 signaling via either genetic alterations or increased expression of proteins regulating mTOR and its downstream targets have contributed to cancer development...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27758884/mtorc2-signaling-drives-the-development-and-progression-of-pancreatic-cancer
#5
David R Driscoll, Saadia A Karim, Makoto Sano, David M Gay, Wright Jacob, Jun Yu, Yusuke Mizukami, Aarthi Gopinathan, Duncan I Jodrell, T R Jeffry Evans, Nabeel Bardeesy, Michael N Hall, Brian J Quattrochi, David S Klimstra, Simon T Barry, Owen J Sansom, Brian C Lewis, Jennifer P Morton
mTOR signaling controls several critical cellular functions and is deregulated in many cancers, including pancreatic cancer. To date, most efforts have focused on inhibiting the mTORC1 complex. However, clinical trials of mTORC1 inhibitors in pancreatic cancer have failed, raising questions about this therapeutic approach. We employed a genetic approach to delete the obligate mTORC2 subunit Rictor and identified the critical times during which tumorigenesis requires mTORC2 signaling. Rictor deletion resulted in profoundly delayed tumorigenesis...
December 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27748764/mtorc1-and-mtorc2-in-cancer-and-the-tumor-microenvironment
#6
L C Kim, R S Cook, J Chen
The mammalian target of rapamycin (mTOR) is a crucial signaling node that integrates environmental cues to regulate cell survival, proliferation and metabolism, and is often deregulated in human cancer. mTOR kinase acts in two functionally distinct complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), whose activities and substrate specificities are regulated by complex co-factors. Deregulation of this centralized signaling pathway has been associated with a variety of human diseases including diabetes, neurodegeneration and cancer...
October 17, 2016: Oncogene
https://www.readbyqxmd.com/read/27729429/mtor-activity-and-its-prognostic-significance-in-human-colorectal-carcinoma-depending-on-c1-and-c2-complex-related-protein-expression
#7
Tamás Sticz, Anna Molnár, Ágnes Márk, Melinda Hajdu, Noémi Nagy, Gyula Végső, Tamás Micsik, László Kopper, Anna Sebestyén
AIMS: Tumour heterogeneity and altered activation of signalling pathways play important roles in therapy resistance. The PI3K/Akt/mTOR signalling network is a well-known regulator of several functions that contribute to tumour growth. mTOR exists in two functionally different multiprotein complexes. We aimed to determine mTOR activity-related proteins in clinically followed, conventionally treated colon carcinomas and to analyse the correlation between clinical data and mTORC1 and mTORC2 activity...
October 11, 2016: Journal of Clinical Pathology
https://www.readbyqxmd.com/read/27649066/calpain-activated-mtorc2-akt-pathway-mediates-airway-smooth-muscle-remodelling-in-asthma
#8
S-S Rao, Q Mu, Y Zeng, P-C Cai, F Liu, J Yang, Y Xia, Q Zhang, L-J Song, L-L Zhou, F-Z Li, Y-X Lin, J Fang, P A Greer, H-Z Shi, W-L Ma, Y Su, H Ye
BACKGROUND: Allergic asthma is characterized by inflammation and airway remodelling. Airway remodelling with excessive deposition of extracellular matrix (ECM) and larger smooth muscle mass are correlated with increased airway responsiveness and asthma severity. Calpain is a family of calcium-dependent endopeptidases, which plays an important role in ECM remodelling. However, the role of calpain in airway smooth muscle remodelling remains unknown. OBJECTIVE: To investigate the role of calpain in asthmatic airway remodelling as well as the underlying mechanism...
September 20, 2016: Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/27563814/molecular-regulation-of-apoptotic-machinery-and-lipid-metabolism-by-mtorc1-mtorc2-dual-inhibitors-in-preclinical-models-of-her2-pik3camut-breast-cancer
#9
Jianchang Qian, Yaqing Chen, Tao Meng, Lanping Ma, Lanfang Meng, Xin Wang, Ting Yu, Arie Zask, Jingkang Shen, Ker Yu
The mechanistic target of rapamycin (mTOR) is a rational target for cancer treatment. While the mTORC1-selective rapalogs have shown significant benefits in the clinic, antitumor response may be further improved by inhibiting both mTORC1 and mTORC2. Herein, we established target profile of a novel mTOR kinase inhibitor (mTOR-KI) MTI-31 and employed it to study new therapeutic mechanism in breast cancer. MTI-31 demonstrated a potent mTOR binding affinity with >5000 fold selectivity over the related PI3K family isoforms...
August 22, 2016: Oncotarget
https://www.readbyqxmd.com/read/27530328/cytotoxic-properties-of-a-deptor-mtor-inhibitor-in-multiple-myeloma-cells
#10
Yijiang Shi, Tracy R Daniels-Wells, Patrick Frost, Jihye Lee, Richard S Finn, Carolyne Bardeleben, Manuel L Penichet, Michael E Jung, Joseph Gera, Alan Lichtenstein
DEPTOR is a 48 kDa protein that binds to mTOR and inhibits this kinase in TORC1 and TORC2 complexes. Overexpression of DEPTOR specifically occurs in a model of multiple myeloma. Its silencing in multiple myeloma cells is sufficient to induce cytotoxicity, suggesting that DEPTOR is a potential therapeutic target. mTORC1 paralysis protects multiple myeloma cells against DEPTOR silencing, implicating mTORC1 in the critical role of DEPTOR in multiple myeloma cell viability. Building on this foundation, we interrogated a small-molecule library for compounds that prevent DEPTOR binding to mTOR in a yeast-two-hybrid assay...
October 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27486771/the-underlying-mechanism-of-proinflammatory-nf-%C3%AE%C2%BAb-activation-by-the-mtorc2-akt-ikk%C3%AE-pathway-during-skin-aging
#11
Yeon Ja Choi, Kyoung Mi Moon, Ki Wung Chung, Ji Won Jeong, Daeui Park, Dae Hyun Kim, Byung Pal Yu, Hae Young Chung
Mammalian target of rapamycin complex 2 (mTORC2), one of two different enzymatic complexes of mTOR, regulates a diverse set of substrates including Akt. mTOR pathway is one of well-known mediators of aging process, however, its role in skin aging has not been determined. Skin aging can be induced by physical age and ultraviolet (UV) irradiation which are intrinsic and extrinsic factors, respectively. Here, we report increased mTORC2 pathway in intrinsic and photo-induced skin aging, which is implicated in the activation of nuclear factor-κB (NF-κB)...
July 29, 2016: Oncotarget
https://www.readbyqxmd.com/read/27477490/roles-of-mtor-complexes-in-the-kidney-implications-for-renal-disease-and-transplantation
#12
REVIEW
Daniel Fantus, Natasha M Rogers, Florian Grahammer, Tobias B Huber, Angus W Thomson
The mTOR pathway has a central role in the regulation of cell metabolism, growth and proliferation. Studies involving selective gene targeting of mTOR complexes (mTORC1 and mTORC2) in renal cell populations and/or pharmacologic mTOR inhibition have revealed important roles of mTOR in podocyte homeostasis and tubular transport. Important advances have also been made in understanding the role of mTOR in renal injury, polycystic kidney disease and glomerular diseases, including diabetic nephropathy. Novel insights into the roles of mTORC1 and mTORC2 in the regulation of immune cell homeostasis and function are helping to improve understanding of the complex effects of mTOR targeting on immune responses, including those that impact both de novo renal disease and renal allograft outcomes...
October 2016: Nature Reviews. Nephrology
https://www.readbyqxmd.com/read/27412013/over-expression-of-dna-pkcs-in-renal-cell-carcinoma-regulates-mtorc2-activation-hif-2%C3%AE-expression-and-cell-proliferation
#13
Bing Zheng, Jia-Hui Mao, Xiao-Qing Li, Lin Qian, Hua Zhu, Dong-Hua Gu, Xiao-Dong Pan
Here, we demonstrated that DNA-PKcs is over-expressed in multiple human renal cell carcinoma (RCC) tissues and in primary/established human RCCs. Pharmacological or genetic inhibition of DNA-PKcs suppressed proliferation of RCC cells. DNA-PKcs was in the complex of mTOR and SIN1, mediating mTORC2 activation and HIF-2α expression in RCC cells. Inhibiting or silencing DNA-PKcs suppressed AKT Ser-473 phosphorylation and HIF-2α expression. In vivo, DNA-PKcs knockdown or oral administration of the DNA-PKcs inhibitor NU-7441 inhibited AKT Ser-473 phosphorylation, HIF-2α expression and 786-0 RCC xenograft growth in nude mice...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27379204/rationally-repurposing-ruxolitinib-jakafi-%C3%A2-as-a-solid-tumor-therapeutic
#14
Mehrad Tavallai, Laurence Booth, Jane L Roberts, Andrew Poklepovic, Paul Dent
We determined whether the approved myelofibrosis drug ruxolitinib (Jakafi(®)), an inhibitor of Janus kinases 1/2 (JAK1 and JAK2), could be repurposed as an anti-cancer agent for solid tumors. Ruxolitinib synergistically interacted with dual ERBB1/2/4 inhibitors to kill breast as well as lung, ovarian and brain cancer cells. Knock down of JAK1/2 or of ERBB1/2/3/4 recapitulated on-target drug effects. The combination of (ruxolitinib + ERBB1/2/4 inhibitor) rapidly inactivated AKT, mTORC1, mTORC2, STAT3, and STAT5, and activated eIF2α...
2016: Frontiers in Oncology
https://www.readbyqxmd.com/read/27338360/role-of-mtor-inhibitors-in-kidney-disease
#15
REVIEW
Moto Kajiwara, Satohiro Masuda
The first compound that inhibited the mammalian target of rapamycin (mTOR), sirolimus (rapamycin) was discovered in the 1970s as a soil bacterium metabolite collected on Easter Island (Rapa Nui). Because sirolimus showed antiproliferative activity, researchers investigated its molecular target and identified the TOR1 and TOR2. The mTOR consists of mTOR complex 1 (mTORC1) and mTORC2. Rapalogues including sirolimus, everolimus, and temsirolimus exert their effect mainly on mTORC1, whereas their inhibitory effect on mTORC2 is mild...
2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27331901/microrna-7-5p-regulates-human-alveolar-epithelial-sodium-channels-by-targeting-the-mtorc2-sgk-1-signaling-pathway
#16
Ke Qin, Xi Zhong, Daoxin Wang
PURPOSE: The aim of this study was to investigate the effect of miRNA-7-5p on human alveolar epithelial sodium channels and clarify the pathway in which miRNA-7-5p regulates the expression of ENaC in ARDS. MATERIALS AND METHODS: Dual luciferase target gene validation experiments were used to confirm whether mTOR and SGK-1 are the target genes of miRNA-7-5p. Then, we overexpressed and inhibited miRNA-7-5p in the human alveolar epithelial cell line A549, respectively...
June 2016: Experimental Lung Research
https://www.readbyqxmd.com/read/27291151/autophagy-induction-contributes-to-gdc-0349-resistance-in-head-and-neck-squamous-cell-carcinoma-hnscc-cells
#17
Yajuan Zhou, Yi Peng, Hao Tang, Xiaojun He, Zhaohua Wang, Desheng Hu, Xiaoyi Zhou
Dysregulation of mammalian target of rapamycin (mTOR) signaling contributes to head and neck squamous cell carcinoma (HNSCC) tumorigenesis and progression. In the current study, we tested the anti-HNSCC cell activity by GDC-0349, a selective ATP-competitive inhibitor of mTOR. We showed that GDC-0349 inhibited proliferation of established and primary human HNSCC cells bearing high-level of p-AKT/p-S6K. Further, it induced caspase-dependent apoptosis in the HNSCC cells. GDC-0349 blocked mTORC1 and mTORC2 activation, yet it simultaneously induced autophagy activation in HNSCC cells...
August 19, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27285754/pi3k-pten-dysregulation-leads-to-mtor-driven-upregulation-of-the-core-clock-gene-bmal1-in-normal-and-malignant-epithelial-cells
#18
Camila S Matsumoto, Luciana O Almeida, Douglas M Guimarães, Manoela D Martins, Petros Papagerakis, Silvana Papagerakis, Andreia M Leopoldino, Rogerio M Castilho, Cristiane H Squarize
Dysfunctional clock signaling is observed in a variety of pathological conditions. Many members of the clock gene family are upregulated in tumor cells. Here, we explored the consequences of a commonly disrupted signaling pathway in head and neck cancer on the regulation of circadian clock genes. PTEN is a key molecular controller of the PI3K signaling, and loss of PTEN function is often observed in a variety of cancers. Our main goal was to determine whether PTEN regulates circadian clock signaling. We found that oxidation-driven loss of PTEN function resulted in the activation of mTOR signaling and activation of the core clock protein BMAL1 (also known as ARNTL)...
July 5, 2016: Oncotarget
https://www.readbyqxmd.com/read/27280401/membrane-tension-acts-through-pld2-and-mtorc2-to-limit-actin-network-assembly-during-neutrophil-migration
#19
Alba Diz-Muñoz, Kevin Thurley, Sana Chintamen, Steven J Altschuler, Lani F Wu, Daniel A Fletcher, Orion D Weiner
For efficient polarity and migration, cells need to regulate the magnitude and spatial distribution of actin assembly. This process is coordinated by reciprocal interactions between the actin cytoskeleton and mechanical forces. Actin polymerization-based protrusion increases tension in the plasma membrane, which in turn acts as a long-range inhibitor of actin assembly. These interactions form a negative feedback circuit that limits the magnitude of membrane tension in neutrophils and prevents expansion of the existing front and the formation of secondary fronts...
June 2016: PLoS Biology
https://www.readbyqxmd.com/read/27239959/pten-negatively-regulates-mtorc2-formation-and-signaling-in-grade-iv-glioma-via-rictor-hyperphosphorylation-at-thr1135-and-direct-the-mode-of-action-of-an-mtorc1-2-inhibitor
#20
K Bhattacharya, S Maiti, C Mandal
To investigate the role of PTEN (phosphatase and tensin homolog) in mammalian target of rapamycin complex 2 (mTORC2) signaling in glioblastoma multiforme (GBM), we found higher activation of mTORC2 in PTEN(mu) cells, as evidenced by enhanced phosphorylation of mTOR (Ser2481), AKT (Ser473) and glycogen synthase kinase 3 beta (GSK3β) (Ser9) as compared with PTEN(wt) cells. In addition, PTEN(wt) cells upon PTEN depletion showed mTORC2 activation. The reduced mTORC2 signaling in PTEN(wt) cells was related to higher Rictor phosphorylation at Thr1135 residue...
2016: Oncogenesis
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