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https://www.readbyqxmd.com/read/27922010/mek-inhibitors-block-growth-of-lung-tumours-with-mutations-in-ataxia-telangiectasia-mutated
#1
Michal Smida, Ferran Fece de la Cruz, Claudia Kerzendorfer, Iris Z Uras, Barbara Mair, Abdelghani Mazouzi, Tereza Suchankova, Tomasz Konopka, Amanda M Katz, Keren Paz, Katalin Nagy-Bojarszky, Markus K Muellner, Zsuzsanna Bago-Horvath, Eric B Haura, Joanna I Loizou, Sebastian M B Nijman
Lung cancer is the leading cause of cancer deaths, and effective treatments are urgently needed. Loss-of-function mutations in the DNA damage response kinase ATM are common in lung adenocarcinoma but directly targeting these with drugs remains challenging. Here we report that ATM loss-of-function is synthetic lethal with drugs inhibiting the central growth factor kinases MEK1/2, including the FDA-approved drug trametinib. Lung cancer cells resistant to MEK inhibition become highly sensitive upon loss of ATM both in vitro and in vivo...
December 6, 2016: Nature Communications
https://www.readbyqxmd.com/read/27920093/metformin-reduces-glycometabolism-of-papillary-thyroid-carcinoma-in-vitro-and-in-vivo
#2
Chen-Tian Shen, Wei-Jun Wei, Zhong-Ling Qiu, Hong-Jun Song, Xin-Yun Zhang, Zhen-Kui Sun, Quan-Yong Luo
More aggressive thyroid cancer cells show a higher activity of glycometabolism. Targeting cancer cell metabolism has emerged as a novel approach to prevent or treat malignant tumors. Glucose metabolism regulation effect of metformin in papillary thyroid cancer was investigated in the current study. Human papillary thyroid carcinoma (PTC) cell lines BCPAP and KTC1 were used. Cell viability was detected by CCK8 assay. Glucose uptake and relative gene expression were measured in metformin (0-10 mM for 48 h)-treated cells by (18)F-FDG uptake assay and western blotting analysis, respectively...
January 2017: Journal of Molecular Endocrinology
https://www.readbyqxmd.com/read/27919208/is-metformin-a-therapeutic-paradigm-for-colorectal-cancer-insight-into-the-molecular-pathway
#3
Zar Chii Thent, Nurul Hannim Zaidun, Fairuz Azmi, Mu Izuddin Senin, Haszianaliza Haslan, Ahmad Ruzain Salehuddin
Colorectal cancer (CRC) remains one of the major leading causes of cancer related morbidity and mortality. Apart from the conventional anti-neoplastic agents, metformin, a biguanide anti-diabetic agent, has recently found to have anti-cancer property. Several studies observed the effect of metformin towards its anti-cancer effect on colon or colorectal cancer in diabetic patients. However, only a few studies showed its effect on colorectal cancer in relation to the non-diabetic status. The present review aimed to highlight the insight into the molecular pathway of metformin towards colorectal cancer in the absence of diabetes mellitus...
December 5, 2016: Current Drug Targets
https://www.readbyqxmd.com/read/27919004/irbesartan-ameliorates-hyperlipidemia-and-liver-steatosis-in-type-2-diabetic-db-db-mice-via-stimulating-ppar-%C3%AE-ampk-akt-mtor-signaling-and-autophagy
#4
Juan Zhong, Wangqiu Gong, Lu Lu, Jing Chen, Zibin Lu, HongYu Li, Wenting Liu, Yangyang Liu, Mingqing Wang, Rong Hu, Haibo Long, Lianbo Wei
Irbesartan (Irb), a unique subset of angiotensin II receptor blockers (ARBs) with PPAR-γ activation function, has been reported to play a role in renal dysfunction, glucose metabolism, and abnormal lipid profile in diabetic animal models and humans. However, the underlying mechanisms that improve hyperlipidemia and liver steatosis are unclear. This study investigated the effects of Irb on lipid metabolism and hepatic steatosis using the spontaneous type 2 diabetic db/db mouse model. The results demonstrated body and liver weight, food consumption, lipid content in serum and liver tissue, and liver dysfunction as well as hepatic steatosis were increased in db/db mice compared with db/m mice, whereas the increases were reversed by Irb treatment...
December 2, 2016: International Immunopharmacology
https://www.readbyqxmd.com/read/27918553/jagged-1-is-a-major-notch-ligand-along-cholangiocarcinoma-development-in-mice-and-humans
#5
L Che, B Fan, M G Pilo, Z Xu, Y Liu, A Cigliano, A Cossu, G Palmieri, R M Pascale, A Porcu, G Vidili, M Serra, F Dombrowski, S Ribback, D F Calvisi, X Chen
Intrahepatic cholangiocarcinoma (ICC) is a rare yet deadly malignancy with limited treatment options. Activation of the Notch signalling cascade has been implicated in cholangiocarcinogenesis. However, while several studies focused on the Notch receptors required for ICC development, little is known about the upstream inducers responsible for their activation. Here, we show that the Jagged 1 (Jag1) ligand is almost ubiquitously upregulated in human ICC samples when compared with corresponding non-tumorous counterparts...
December 5, 2016: Oncogenesis
https://www.readbyqxmd.com/read/27918305/tuberous-sclerosis-complex-inactivation-disrupts-melanogenesis-via-mtorc1-activation
#6
Juxiang Cao, Magdalena E Tyburczy, Joel Moss, Thomas N Darling, Hans R Widlund, David J Kwiatkowski
Tuberous sclerosis complex (TSC) is an autosomal dominant tumor-suppressor gene syndrome caused by inactivating mutations in either TSC1 or TSC2, and the TSC protein complex is an essential regulator of mTOR complex 1 (mTORC1). Patients with TSC develop hypomelanotic macules (white spots), but the molecular mechanisms underlying their formation are not fully characterized. Using human primary melanocytes and a highly pigmented melanoma cell line, we demonstrate that reduced expression of either TSC1 or TSC2 causes reduced pigmentation through mTORC1 activation, which results in hyperactivation of glycogen synthase kinase 3β (GSK3β), followed by phosphorylation of and loss of β-catenin from the nucleus, thereby reducing expression of microphthalmia-associated transcription factor (MITF), and subsequent reductions in tyrosinase and other genes required for melanogenesis...
December 5, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27918097/sugars-and-fat-a-healthy-way-to-generate-functional-regulatory-t-cells
#7
Sarah Sharon Gabriel, Axel Kallies
Cellular metabolism has emerged as an important regulator of adaptive immunity. While the metabolic requirements of conventional T cells are increasingly understood, the role of cellular metabolism in Foxp3(+) regulatory T (Treg) cells is less clear. Although it is well accepted that repression of Akt/mTOR, HIF-1α and aerobic glycolysis are important for the efficient generation of Treg cells in vitro, clear evidence how these pathways impact on Treg-cell development in vivo is limited. Furthermore, newer studies have shown that the same pathways that appear to suppress Treg-cell development are active in and required for functionally mature Treg cells...
December 2016: European Journal of Immunology
https://www.readbyqxmd.com/read/27915972/resistance-to-cell-death-and-its-modulation-in-cancer-stem-cells
#8
Ahmad R Safa
Accumulating evidence has demonstrated that human cancers arise from various tissues of origin that initiate from cancer stem cells (CSCs) or cancer-initiating cells. The extrinsic and intrinsic apoptotic pathways are dysregulated in CSCs, and these cells play crucial roles in tumor initiation, progression, cell death resistance, chemo- and radiotherapy resistance, and tumor recurrence. Understanding CSC-specific signaling proteins and pathways is necessary to identify specific therapeutic targets that may lead to the development of more efficient therapies selectively targeting CSCs...
2016: Critical Reviews in Oncogenesis
https://www.readbyqxmd.com/read/27914215/lysine-specific-demethylase-1-lsd1-inhibitor-s2101-induces-autophagy-via-the-akt-mtor-pathway-in-skov3-ovarian-cancer-cells
#9
Shujun Feng, Ye Jin, Mengjiao Cui, Jianhua Zheng
BACKGROUND S2101 is one of the most potent LSD1 inhibitors, which can inhibit ovarian cancer cells viability. This study aimed to detect the mechanism behind the anticancer properties of S2101 in SKOV3 ovarian cells. MATERIAL AND METHODS Cell viability was tested by Cell Counting Kit-8 (CCK-8) assay. Cellular apoptosis and autophagy were evaluated by flow cytometric analysis using Annexin-V/PI staining methods and Green fluorescent protein (GFP)-fused-LC3 (GFP-LC3), respectively. Western blotting was performed for analyzing the Bax, Bcl-2, mTOR, p- mTOR, p62, LC3-I, LC3-II, AKT, and p-AKT protein expression...
December 3, 2016: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/27913532/t-cell-acute-lymphoblastic-leukemia
#10
Elizabeth A Raetz, David T Teachey
T-cell acute lymphoblastic leukemia (T-ALL) is biologically distinct from its B lymphoblastic (B-ALL) counterpart and shows different kinetic patterns of disease response. Although very similar regimens are used to treat T-ALL and B-ALL, distinctions in response to different elements of therapy have been observed. Similar to B-ALL, the key prognostic determinant in T-ALL is minimal residual disease (MRD) response. Unlike B-ALL, other factors including age, white blood cell count at diagnosis, and genetics of the ALL blasts are not independently prognostic when MRD response is included...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27912873/pomolic-acid-suppresses-hif1%C3%AE-vegf-mediated-angiogenesis-by-targeting-p38-mapk-and-mtor-signaling-cascades
#11
Ji-Hyun Park, Jaewoo Yoon, Byoungduck Park
BACKGROUND: Pomolic acid (PA), an active triterpenoid from Euscaphis japonica, inhibits the proliferation of a variety of cancer cells, but the molecular mechanisms of the anti-angiogenic potential of PA have not been fully elucidated in breast cancer cells. HYPOTHESIS/PURPOSE: We investigated the molecular mechanisms underlying the anti-angiogenic effect of PA in epidermal growth factor (EGF)-responsive human breast cancer cells, MCF-7 and MDA-MB-231, and human umbilical vascular endothelial cells (HUVEC)...
December 15, 2016: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/27911920/sirna-targeting-mtor-effectively-prevents-the-proliferation-and-migration-of-human-lens-epithelial-cells
#12
Chunmei Zhang, Jingjing Liu, Na Jin, Guiming Zhang, Yahui Xi, Hongling Liu
Posterior capsule opacification (PCO) is the most common complication that causes visual decrease after extracapsular cataract surgery. The primary cause of PCO formation is the proliferation of the residual lens epithelial cells (LECs). The mammalian target of rapamycin (mTOR) plays an important role in the growth and migration of LECs. In the current study, we used small interfering RNA (siRNA) to specifically attenuate mTOR in human lens epithelial B3 cells (HLE B3). We aimed to examine the effect of mTOR-siRNA on the proliferation, migration and epithelial-to-mesenchymal transition (EMT) of HLE B3 cells and explore the underlying mechanisms...
2016: PloS One
https://www.readbyqxmd.com/read/27910068/endometrial-carcinoma-specific-targeted-pathways
#13
Nuria Eritja, Andree Yeramian, Bo-Juen Chen, David Llobet-Navas, Eugenia Ortega, Eva Colas, Miguel Abal, Xavier Dolcet, Jaume Reventos, Xavier Matias-Guiu
Endometrial cancer (EC) is the most common gynecologic malignancy in the western world with more than 280,000 cases per year worldwide. Prognosis for EC at early stages, when primary surgical resection is the most common initial treatment, is excellent. Five-year survival rate is around 70 %.Several molecular alterations have been described in the different types of EC. They occur in genes involved in important signaling pathways. In this chapter, we will review the most relevant altered pathways in EC, including PI3K/AKT/mTOR, RAS-RAF-MEK-ERK, Tyrosine kinase, WNT/β-Catenin, cell cycle, and TGF-β signaling pathways...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/27906498/st3gal6-mediates-the-effect-of-mir-26a-on-cell-growth-migration-and-invasion-in-hepatocellular-carcinoma-via-the-akt-mtor-pathway
#14
Mingming Sun, Xuzi Zhao, Leilei Liang, Xufeng Pan, Hao Lv, Yongfu Zhao
Aberrant sialylation profiles on the cell surface have been recognized for their potential diagnostic value in identifying the regulation of tumor properties in several cancers, including hepatocellular carcinoma (HCC). Recently, increasing evidence has suggested that the deregulation of microRNA (miRNA) is a common feature in human cancers. In this study, we found obvious up-regulation of ST3GAL6 both in HCC cell lines and in tissue samples. The altered expression of ST3GAL6 was found to correlate with cell proliferation, migration and invasion ability in HCC...
December 1, 2016: Cancer Science
https://www.readbyqxmd.com/read/27906078/four-week-rapamycin-treatment-improves-muscular-dystrophy-in-a-fukutin-deficient-mouse-model-of-dystroglycanopathy
#15
Steven J Foltz, Junna Luan, Jarrod A Call, Ankit Patel, Kristen B Peissig, Marisa J Fortunato, Aaron M Beedle
BACKGROUND: Secondary dystroglycanopathies are a subset of muscular dystrophy caused by abnormal glycosylation of α-dystroglycan (αDG). Loss of αDG functional glycosylation prevents it from binding to laminin and other extracellular matrix receptors, causing muscular dystrophy. Mutations in a number of genes, including FKTN (fukutin), disrupt αDG glycosylation. METHODS: We analyzed conditional Fktn knockout (Fktn KO) muscle for levels of mTOR signaling pathway proteins by Western blot...
June 2, 2016: Skeletal Muscle
https://www.readbyqxmd.com/read/27905484/independent-control-of-natural-killer-cell-responsiveness-and-homeostasis-at-steady-state-by-cd11c-dendritic-cells
#16
Thuy Thanh Luu, Sridharan Ganesan, Arnika Kathleen Wagner, Dhifaf Sarhan, Stephan Meinke, Natalio Garbi, Günter Hämmerling, Evren Alici, Klas Kärre, Benedict J Chambers, Petter Höglund, Nadir Kadri
During infection and inflammation, dendritic cells (DC) provide priming signals for natural killer (NK) cells via mechanisms distinct from their antigen processing and presentation functions. The influence of DC on resting NK cells, i.e. at steady-state, is less well studied. We here demonstrate that as early as 1 day after DC depletion, NK cells in naïve mice downregulated the NKG2D receptor and showed decreased constitutive phosphorylation of AKT and mTOR. Subsequently, apoptotic NK cells appeared in the spleen concomitant with reduced NK cell numbers...
December 1, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27905110/distinct-molecular-landscapes-between-endometrioid-and-non-endometrioid-uterine-carcinomas
#17
Nathaniel L Jones, Joanne Xiu, Sudeshna Chatterjee-Paer, Alexandre Buckley de Meritens, William M Burke, Ana I Tergas, Jason D Wright, June Y Hou
Endometrial carcinoma (EC) is traditionally characterized as endometrioid and non-endometrioid based on histo-pathologic phenotypes. Molecular-based classifications have been proposed, but are not widely implemented. Herein we examine molecular profiles between EC histologic subtypes. 3133 ECs were submitted between March 2011 and July 2014: 1634 Type I and 1226 Type II. In situ hybridization and immunohistochemistry were used to assess copy number and protein expression of selected genes. Sequenced variants in 47 genes were analyzed using the Illumina TruSeq Amplicon Cancer Panel...
December 1, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27904994/rapamycin-protects-sepsis-induced-cognitive-impairment-in-mouse-hippocampus-by-enhancing-autophagy
#18
Wenyu Liu, Jia'nan Guo, Jie Mu, Linyu Tian, Dong Zhou
The purpose of this study is to test the hypothesis that the mammalian target of rapamycin (mTOR) signaling pathway might mediate neuroprotection in a mouse model of septic encephalopathy and also to identify the role of autophagy. Mice were subjected to cecal ligation and puncture (CLP) or a sham operation, and all 50 mice were randomly assigned to five groups: sham, CLP+ saline, CLP+ rapamycin (1, 5, 10 mg/kg) groups. Two weeks after the operation, Morris water maze was conducted for behavioral test; Nissl staining was used for observing glia infiltration; immunohistochemical staining and biochemical measures in hippocampi were performed to detect mTOR targets and autophagy indicators...
December 1, 2016: Cellular and Molecular Neurobiology
https://www.readbyqxmd.com/read/27904496/adipose-derived-stem-cells-enhance-myogenic-differentiation-in-the-mdx-mouse-model-of-muscular-dystrophy-via-paracrine-signaling
#19
Ji-Qing Cao, Ying-Yin Liang, Ya-Qin Li, Hui-Li Zhang, Yu-Ling Zhu, Jia Geng, Li-Qing Yang, Shan-Wei Feng, Juan Yang, Jie Kong, Cheng Zhang
Adipose-derived stem cells have been shown to promote peripheral nerve regeneration through the paracrine secretion of neurotrophic factors. However, it is unclear whether these cells can promote myogenic differentiation in muscular dystrophy. Adipose-derived stem cells (6 × 10(6)) were injected into the gastrocnemius muscle of mdx mice at various sites. Dystrophin expression was found in the muscle fibers. Phosphorylation levels of Akt, mammalian target of rapamycin (mTOR), eIF-4E binding protein 1 and S6 kinase 1 were increased, and the Akt/mTOR pathway was activated...
October 2016: Neural Regeneration Research
https://www.readbyqxmd.com/read/27903983/dyrk1b-blocks-canonical-and-promotes-non-canonical-hedgehog-signaling-through-activation-of-the-mtor-akt-pathway
#20
Rajeev Singh, Pavan Kumar Dhanyamraju, Matthias Lauth
Hedgehog (Hh) signaling plays important roles in embryonic development and in tumor formation. Apart from the well-established stimulation of the GLI family of transcription factors, Hh ligands promote the phosphorylation and activation of mTOR and AKT kinases, yet the molecular mechanism underlying these processes are unknown. Here, we identify the DYRK1B kinase as a mediator between Hh signaling and mTOR/AKT activation. In fibroblasts, Hh signaling induces DYRK1B protein expression, resulting in activation of the mTOR/AKT kinase signaling arm...
November 26, 2016: Oncotarget
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