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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/27919208/is-metformin-a-therapeutic-paradigm-for-colorectal-cancer-insight-into-the-molecular-pathway
#2
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
#3
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
#4
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
#5
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/27917698/tetramethylpyrazine-protects-against-glucocorticoid-induced-apoptosis-by-promoting-autophagy-in-mesenchymal-stem-cells-and-improves-bone-mass-in-glucocorticoid-induced-osteoporosis-rats
#6
Long Wang, Hong-Yang Zhang, Bo Gao, Jun Shi, Qiang Huang, Yue-Hu Han, Ya-Qian Hu, Wei-Guang Lu, Zhuo-Jie Zhao, Bao-Hua Liu, Qiang Jie, Liu Yang, Zhuo-Jing Luo
Glucocorticoid-induced osteoporosis (GIOP) is a widespread clinical complication due to the common use of glucocorticoids. Excess glucocorticoids induce apoptosis of bone marrow-derived mesenchymal stem cells (BMSCs), which have been shown to play an increasingly important role in the pathogenesis and therapy of osteoporosis. Tetramethylpyrazine (TMP), an extract from one of the most recognized herbs in traditional Chinese medicine (Chuanxiong), has been reported to have anti-apoptotic properties. In this study, we tested whether TMP protects rat BMSCs following exposure to glucocorticoids in vitro and in vivo...
December 4, 2016: Stem Cells and Development
https://www.readbyqxmd.com/read/27916907/metformin-inhibits-tgf-%C3%AE-1-induced-epithelial-to-mesenchymal-transition-via-pkm2-relative-mtor-p70s6k-signaling-pathway-in-cervical-carcinoma-cells
#7
Keyan Cheng, Min Hao
BACKGROUND: Epithelial-to-mesenchymal transition (EMT) plays a prominent role in tumorigenesis. Metformin exerts antitumorigenic effects in various cancers. This study investigated the mechanisms of metformin in TGF-β1-induced Epithelial-to-mesenchymal transition (EMT) in cervical carcinoma cells. METHODS: cells were cultured with 10 ng/mL TGF-β1 to induce EMT and treated with or without metformin. Cell viability was evaluated by CCK-8 (Cell Counting Kit 8, CCK-8) assay; apoptosis were analyzed by flow cytometry; cell migration was evaluated by wound-healing assay...
November 30, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27914823/rapamycin-inhibits-the-proliferation-of-endothelial-cells-in-hemangioma-by-blocking-the-mtor-fabp4-pathway
#8
Ying Wang, Jiarui Chen, Weiqing Tang, Yanping Zhang, Xiaoyan Li
FABP4 is widely expressed in both normal and pathologic tissues. It promotes cell proliferation, survival and migration of endothelial cells, and therefore, angiogenesis. However, the role of FABP4 in hemangioma or hemangioma endothelial cells (HemECs) has not been explored. In this study, we investigated whether FABP4 directly regulates the proliferation of HemECs. The expression of cell cycle checkpoint genes was analyzed with the microarray data of human dermal microvascular endothelial cells (HDVECs) and infantile hemangioma endothelial cells...
November 30, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
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/27913676/translational-control-by-mtor-independent-routes-how-eif6-organizes-metabolism
#10
REVIEW
Annarita Miluzio, Sara Ricciardi, Nicola Manfrini, Roberta Alfieri, Stefania Oliveto, Daniela Brina, Stefano Biffo
Over the past few years, there has been a growing interest in the interconnection between translation and metabolism. Important oncogenic pathways, like those elicited by c-Myc transcription factor and mTOR kinase, couple the activation of the translational machinery with glycolysis and fatty acid synthesis. Eukaryotic initiation factor 6 (eIF6) is a factor necessary for 60S ribosome maturation. eIF6 acts also as a cytoplasmic translation initiation factor, downstream of growth factor stimulation. eIF6 is up-regulated in several tumor types...
December 15, 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/27913436/erk-and-p38-mapk-activities-determine-sensitivity-to-pi3k-mtor-inhibition-via-regulation-of-myc-and-yap
#11
Taru Muranen, Laura M Selfors, Julie Hwang, Lisa L Gallegos, Jonathan L Coloff, Carson C Thoreen, Seong A Kang, David M Sabatini, Gordon B Mills, Joan S Brugge
Aberrant activation of the PI3K/mTOR pathway is a common feature of many cancers and an attractive target for therapy, but resistance inevitably evolves as is the case for any cancer cell-targeted therapy. In animal tumor models, chronic inhibition of PI3K/mTOR initially inhibits tumor growth, but over time, tumor cells escape inhibition. In this study, we identified a context-dependent mechanism of escape whereby tumor cells upregulated the proto-oncogene transcriptional regulators c-MYC and YAP1. This mechanism was dependent on both constitutive ERK activity as well as inhibition of the stress kinase p38...
October 20, 2016: Cancer Research
https://www.readbyqxmd.com/read/27913296/regulation-of-skeletal-muscle-insulin-stimulated-signaling-through-the-mek-redd1-mtor-axis
#12
Cory M Dungan, David L Williamson
Recent findings in adipocytes suggest that mitogen-activated protein kinase (MAPK)/extracellular-regulated signaling kinase (ERK) kinase 1/2 (MEK1/2) signaling regulates regulated in development and DNA damage 1 (REDD1) protein expression. Similarly, our previous work show that a lack of REDD1 protein expression, and associated hyperactive basal mechanistic target of rapamycin (mTOR) signaling, limits skeletal muscle's response to insulin. Therefore, we sought to determine: 1) if MEK1/2 inhibition is sufficient to reduce REDD1 protein expression and subsequently insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation via negative feedback of hyperactive mTOR in REDD1 wild-type (WT) mice and 2) if rapamycin-mediated mTOR inhibition is sufficient to improve IRS-1 tyrosine phosphorylation in REDD1 knockout (KO) mice...
November 29, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27912873/pomolic-acid-suppresses-hif1%C3%AE-vegf-mediated-angiogenesis-by-targeting-p38-mapk-and-mtor-signaling-cascades
#13
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
#14
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/27908730/mtor-activation-is-critical-for-betulin-treatment-in-renal-cell-carcinoma-cells
#15
Wenlong Cheng, Shiqi Ji, Haijian Zhang, Zhixing Han, Qingjun Liu, Jianwen Wang, Hao Ping
Betulin, a natural product isolated from the bark of the birch trees, exhibits multiple anticancer effects. Activation of mTOR signaling pathway has been found in numerous cancers, including renal cell carcinoma (RCC). Here, we attempted to study whether mTOR signaling was essential for betulin to treat RCC. Based on cell survival and colony formation assays, we found that mTOR hyperactive RCC cell line 786-O cells were more sensitive to betulin treatment compared with mTOR-inactive Caki-2 cells. Knockdown of TSC2 in Caki-2 cells had similar results to 786-O cells, and mTOR silencing in 786-O cells rescued the inhibitory effect of betulin, indicating that betulin inhibited RCC cell proliferation in an mTOR-dependent manner...
November 28, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27906677/the-implication-of-flt3-amplification-for-flt-targeted-therapeutics-in-solid-tumors
#16
Sung Hee Lim, Sun-Young Kim, Kyung Kim, Hyojin Jang, Soomin Ahn, Kyoung-Mee Kim, Nayoung K D Kim, Woongyang Park, Su Jin Lee, Seung Tae Kim, Se Hoon Park, Joon Oh Park, Young Suk Park, Se-Hoon Lee, Ho Yeong Lim, Keunchil Park, Won Ki Kang, Jeeyun Lee
We investigated the patients with solid cancers harboring Fms-like tyrosine kinase 3 (FLT3) amplification using targeted sequencing of tumor tissue specimen and FISH assay. Simultaneously, FLT3-amplified patient-derived cells (PDCs) were generated to evaluate the sensitivity to FLT3 inhibition. A patient with metastatic colon cancer who was previously treated with more than 3rd line cytotoxic chemotherapy was found to have FLT3 amplification and then received regorafenib showing partial response. In two PDC cell lines with FLT3 amplification, FLT3 mRNA expression was increased, however, the growth of tumor cells was not significantly inhibited by either regorafenib or sorafenib which is known to block the activity FLT3...
November 29, 2016: Oncotarget
https://www.readbyqxmd.com/read/27906078/four-week-rapamycin-treatment-improves-muscular-dystrophy-in-a-fukutin-deficient-mouse-model-of-dystroglycanopathy
#17
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/27906072/actrii-blockade-protects-mice-from-cancer-cachexia-and-prolongs-survival-in-the-presence-of-anti-cancer-treatments
#18
Shinji Hatakeyama, Serge Summermatter, Marie Jourdain, Stefan Melly, Giulia C Minetti, Estelle Lach-Trifilieff
BACKGROUND: Cachexia affects the majority of patients with advanced cancer and is associated with reduced treatment tolerance, response to therapy, quality of life, and life expectancy. Cachectic patients with advanced cancer often receive anti-cancer therapies against their specific cancer type as a standard of care, and whether specific ActRII inhibition is efficacious when combined with anti-cancer agents has not been elucidated yet. METHODS: In this study, we evaluated interactions between ActRII blockade and anti-cancer agents in CT-26 mouse colon cancer-induced cachexia model...
July 26, 2016: Skeletal Muscle
https://www.readbyqxmd.com/read/27904994/rapamycin-protects-sepsis-induced-cognitive-impairment-in-mouse-hippocampus-by-enhancing-autophagy
#19
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/27904667/icaritin-induces-apoptotic-and-autophagic-cell-death-in-human-glioblastoma-cells
#20
Zhaopei Li, Xiangwen Meng, Lin Jin
BACKGROUND: GBM represents the most aggressive type of glioma which is featured by extremely aggressive invasion and destructive malignancy with a high proliferation rate. The aim of this study was to investigate the in vitro anti-tumor effect of icaritin in human GBM cell line U87. METHODS: The effect of icaritin on In vitro cell viability was determined by MTT assay and colony formation assay. The inducing effect of icaritin on cell cycle arrest, mitochondrial membrane potential loss, apoptosis, autophagy and intracellular ROS generation was assessed by flow cytometry...
2016: American Journal of Translational Research
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