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Lactate AND mTOR

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https://www.readbyqxmd.com/read/28214879/thiamine-deprivation-produces-a-liver-atp-deficit-and-metabolic-and-genomic-effects-in-mice-findings-are-parallel-to-those-of-biotin-deficiency-and-have-implications-for-energy-disorders
#1
Alain de J Hernandez-Vazquez, Josue Andres Garcia-Sanchez, Elizabeth Moreno-Arriola, Ana Salvador-Adriano, Daniel Ortega-Cuellar, Antonio Velazquez-Arellano
Thiamine is one of several essential cofactors for ATP generation. Its deficiency, like in beriberi and in the Wernicke-Korsakoff syndrome, has been studied for many decades. However, its mechanism of action is still not completely understood at the cellular and molecular levels. Since it acts as a coenzyme for dehydrogenases of pyruvate, branched-chain keto acids, and ketoglutarate, its nutritional privation is partly a phenocopy of inborn errors of metabolism, among them maple syrup urine disease. In the present paper, we report metabolic and genomic findings in mice deprived of thiamine...
February 18, 2017: Journal of Nutrigenetics and Nutrigenomics
https://www.readbyqxmd.com/read/28187451/gsk1059615-kills-head-and-neck-squamous-cell-carcinoma-cells-possibly-via-activating-mitochondrial-programmed-necrosis-pathway
#2
Jing Xie, Quan Li, Xi Ding, Yunyun Gao
This study tested the anti-head and neck squamous cell carcinoma (HNSCC) cell activity by GSK1059615, a novel PI3K and mTOR dual inhibitor. GSK1059615 inhibited survival and proliferation of established (SCC-9, SQ20B and A253 lines) and primary human HNSCC cells. GSK1059615 blocked PI3K-AKT-mTOR activation in HNSCC cells. Intriguingly, GSK1059615 treatment in HNSCC cells failed to provoke apoptosis, but induced programmed necrosis. The latter was tested by mitochondria depolarization, ANT-1-cyclophilin-D mitochondrial association and lactate dehydrogenase (LDH) release...
February 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28181145/low-after-high-glucose-down-regulated-cx43-in-h9c2-cells-by-autophagy-activation-via-cross-regulation-by-the-pi3k-akt-mtor-and-mek-erk1-2-signal-pathways
#3
Yaguang Bi, Guangyu Wang, Xiangdong Liu, Meng Wei, Qingyong Zhang
PURPOSE: Hypoglycemia in diabetes is a strong predictor of cardiovascular events. High-glucose have been reported to alter connexin43 expression and to promote autophagy in cardiomyocytes. We investigated whether low-after-high glucose would influence connexin43 expression and autophagy in H9c2 cells. METHODS: H9c2 cells were incubated in 33.3 mM glucose for 24 h followed by 2.5 mM glucose for 2, 4, 6, or 12 h with or without chloroquine (autophagy inhibitor), U0126 (MEK1/2 inhibitor) or LY294002 (PI3K inhibitor)...
February 8, 2017: Endocrine
https://www.readbyqxmd.com/read/28174256/a-time-for-myc-metabolism-and-therapy
#4
Chi V Dang
The MYC oncogene is frequently deregulated in human cancers, whereas the proto-oncogene is exquisitely, tightly regulated in normal cells. Deregulated MYC drives transcriptional imbalance, thereby altering metabolism and disrupting the circadian Bmal1-Clock E-box-dependent transcriptional circuitry. Sustained oncogenic MYC expression drives a constitutive growth program with mammalian target of rapamycin (mTOR) activation that renders cells dependent on nutrients, such that glucose or glutamine deprivation could trigger cell death and key enzymes such as lactate dehydrogenase A (LDHA) and glutaminase (GLS) amenable for targeting in cancers...
February 7, 2017: Cold Spring Harbor Symposia on Quantitative Biology
https://www.readbyqxmd.com/read/28126648/maternal-consumption-of-low-isoflavone-soy-protein-isolate-alters-hepatic-gene-expression-and-liver-development-in-rat-offspring
#5
Sae Bom Won, Anna Han, Young Hye Kwon
In utero environment is known to affect fetal development. Especially, the distinct fetal programming of carcinogenesis was reported in offspring exposed to maternal diets containing soy protein isolate (SPI) or genistein. Therefore, we investigated whether maternal consumption of low-isoflavone SPI or genistein alters hepatic gene expression and liver development in rat offspring. Female Sprague-Dawley rats were fed a casein diet, a low-isoflavone SPI diet or a casein diet supplemented with genistein (250 mg/kg diet) for 2 weeks before mating and throughout pregnancy and lactation...
January 12, 2017: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/28118663/the-effects-of-nonporous-silica-nanoparticles-on-cultured-human-keratocytes
#6
Bora Yim, Joo-Hee Park, Hyejoong Jeong, Jinkee Hong, Young-Joo Shin, Roy S Chuck, Choul Yong Park
Purpose: Silica nanoparticles (SiNPs) are promising carriers for ophthalmic drug delivery. In this study, we investigated the effect of various sizes of nonporous SiNPs on cultured human keratocytes. Methods: Three different sizes of SiNPs (50, 100, and 150 nm) were manufactured. Primarily cultured human keratocytes were exposed to different concentrations (0, 25, 50, and 100 μg/mL) of three sizes of SiNPs for up to 72 hours. Intracellular reactive oxygen species (ROS) generation, cellular viability, lactate dehydrogenase (LDH) assay, autophagy, vimentin expression, and mammalian target of rapamycin (mTOR) pathway activation were evaluated...
January 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28052008/targeting-p-glycoprotein-function-p53-and-energy-metabolism-combination-of-metformin-and-2-deoxyglucose-reverses-the-multidrug-resistance-of-mcf-7-dox-cells-to-doxorubicin
#7
Chaojun Xue, Changyuan Wang, Yaoting Sun, Qiang Meng, Zhihao Liu, Xiaokui Huo, Pengyuan Sun, Huijun Sun, Xiaodong Ma, Xiaochi Ma, Jinyong Peng, Kexin Liu
Multidrug resistance(MDR) is a major obstacle to efficiency of breast cancer chemotherapy. We investigated whether combination of metformin and 2-deoxyglucose reverses MDR of MCF-7/Dox cells and tried to elucidate the possible mechanisms. The combination of metformin and 2-deoxyglucose selectively enhanced cytotoxicity of doxorubicin against MCF-7/Dox cells. Combination of the two drugs resumed p53 function via inhibiting overexpression of murine doubleminute 2(MDM2) and murine doubleminute 4(MDM4) leading to G2/M arrest and apoptosis in MCF-7/Dox cells...
January 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/27991931/oxidative-stress-downstream-of-mtorc1-but-not-akt-causes-a-proliferative-defect-in-cancer-cells-resistant-to-pi3k-inhibition
#8
M Dermit, P Casado, V Rajeeve, E H Wilkes, D E Foxler, H Campbell, S Critchlow, T V Sharp, J G Gribben, R Unwin, P R Cutillas
Compounds targeting phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling are being investigated in multiple clinical settings, but drug resistance may reduce their benefit. Compound rechallenge after drug holidays can overcome such resistance, yet little is known about the impact of drug holidays on cell biochemistry. We found that PI3K inhibitor (PI3Ki)-resistant cells cultured in the absence of PI3Ki developed a proliferative defect, increased oxygen consumption and accumulated reactive oxygen species (ROS), leading to lactate production through hypoxia-inducible factor-1α...
December 19, 2016: Oncogene
https://www.readbyqxmd.com/read/27983688/maternal-food-restriction-during-pregnancy-and-lactation-adversely-affect-hepatic-growth-and-lipid-metabolism-in-three-week-old-rat-offspring
#9
Sangmi Lee, Young-Ah You, Eun Jin Kwon, Sung-Chul Jung, Inho Jo, Young Ju Kim
Maternal malnutrition influences the early development of foetal adaptive changes for survival. We explored the effects of maternal undernutrition during gestation and lactation on hepatic growth and function. Sprague-Dawley rats were fed a normal or a food-restricted (FR) diet during gestation and/or lactation. We performed analyses of covariance (adjusting for the liver weight/body weight ratio) to compare hepatic growth and lipid metabolism among the offspring. Maternal FR during gestation triggered the development of wide spaces between hepatic cells and increased the expression of mammalian target of rapamycin (mTOR) in three-week-old male offspring compared with controls (both p < 0...
December 15, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27908730/mtor-activation-is-critical-for-betulin-treatment-in-renal-cell-carcinoma-cells
#10
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...
January 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27900044/plumbagin-inhibits-cell-proliferation-and-promotes-apoptosis-in-multiple-myeloma-cells-through-inhibition-of-the-pi3k-akt-mtor-pathway
#11
Hongwei Wu, Xiaozhen Dai, Enren Wang
Plumbagin is the primary component of the traditional Chinese medicine Baihua Dan, and possesses anti-infection and anticancer effects with the ability to enhance the sensitivity of tumor cells to radiation therapy. The present study aimed to investigate the potential anticancer effect and mechanism of plumbagin on multiple myeloma (MM) cells. Human MM OPM1 cells were treated with plumbagin, and its impact on cell viability, cytotoxicity, apoptosis and caspase-3 activity was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, lactate dehydrogenase leakage, flow cytometry and colorimetric assays...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27698900/anti-inflammatory-and-antitumor-activity-of-a-triple-therapy-for-a-colitis-related-colorectal-cancer
#12
Gabriela Figueroa-González, Verónica García-Castillo, Jossimar Coronel-Hernández, Eduardo López-Urrutia, Sonia León-Cabrera, Luis E Arias-Romero, L I Terrazas, Miriam Rodríguez-Sosa, Alma Delia Campos-Parra, Eduardo Zúñiga-Calzada, Cesar Lopez-Camarillo, Fermín Morales-González, Nadia J Jacobo-Herrera, Carlos Pérez-Plasencia
Colorectal cancer (CRC) is an important health issue worldwide, accounting for the third place of cancer incidence. Chronic inflammation, as seen in Crohn's disease and ulcerative colitis, is the most important risk factor for developing CRC, as it favours neoplastic transformation by enhancing epithelial cell turnover in the colonic mucosa. Treatments for CRC need to be improved; currently they are not specific and have several secondary effects in patients. The main objective of this work was to evaluate a new therapeutic strategy against a colitis-related colorectal cancer in vivo and in vitro by targeting mTOR-signaling and lactate dehydrogenase A...
2016: Journal of Cancer
https://www.readbyqxmd.com/read/27666003/basal-autophagy-protects-cardiomyocytes-from-doxorubicin-induced-toxicity
#13
Marcela Pizarro, Rodrigo Troncoso, Gonzalo J Martínez, Mario Chiong, Pablo F Castro, Sergio Lavandero
Doxorubicin (Doxo) is one of the most effective anti-neoplastic agents but its cardiotoxicity has been an important clinical limitation. The major mechanism of Doxo-induced cardiotoxicity is associated to its oxidative capacity. However, other processes are also involved with significant consequences for the cardiomyocyte. In recent years, a number of studies have investigated the role of autophagy on Doxo-induced cardiotoxicity but to date it is not clear how Doxo alters that process and its consequence on cardiomyocytes viability...
September 22, 2016: Toxicology
https://www.readbyqxmd.com/read/27602585/human-cytomegalovirus-encoded-chemokine-receptor-us28-activates-the-hif-1%C3%AE-pkm2-axis-in-glioblastoma-cells
#14
Raymond H de Wit, Azra Mujić-Delić, Jeffrey R van Senten, Alberto Fraile-Ramos, Marco Siderius, Martine J Smit
The human cytomegalovirus (HCMV) encoded chemokine receptor US28 promotes tumorigenesis through activation of various proliferative and angiogenic signaling pathways. Upon infection, US28 displays constitutive activity and signals in a G protein-dependent manner, hijacking the host's cellular machinery. In tumor cells, the hypoxia inducible factor-1α/pyruvate kinase M2 (HIF-1α/PKM2) axis plays an important role by supporting proliferation, angiogenesis and reprogramming of energy metabolism. In this study we show that US28 signaling results in activation of the HIF-1α/PKM2 feedforward loop in fibroblasts and glioblastoma cells...
October 18, 2016: Oncotarget
https://www.readbyqxmd.com/read/27498786/nitidine-chloride-inhibits-the-malignant-behavior-of-human-glioblastoma-cells-by-targeting-the-pi3k-akt-mtor-signaling-pathway
#15
Ming Liu, Jiwei Wang, Qichao Qi, Bin Huang, Anjing Chen, Xingang Li, Jian Wang
Recent studies have demonstrated that nitidine chloride (NC), a natural bioactive alkaloid, displays potent antitumor activity in various types of cancer. In the present study, NC was examined for efficacy in the treatment of human glioblastoma multiforme (GBM) as well as the molecular basis for its more general inhibitory effects in cancer. U251 and U87 GBM cell lines were exposed to three concentrations of NC (5, 25 and 50 µM) in vitro, and tumor cell growth was assessed on the basis of proliferation, migration and energy metabolism...
October 2016: Oncology Reports
https://www.readbyqxmd.com/read/27479743/metabolic-plasticity-underpins-innate-and-acquired-resistance-to-ldha-inhibition
#16
Aaron Boudreau, Hans E Purkey, Anna Hitz, Kirk Robarge, David Peterson, Sharada Labadie, Mandy Kwong, Rebecca Hong, Min Gao, Christopher Del Nagro, Raju Pusapati, Shuguang Ma, Laurent Salphati, Jodie Pang, Aihe Zhou, Tommy Lai, Yingjie Li, Zhongguo Chen, Binqing Wei, Ivana Yen, Steve Sideris, Mark McCleland, Ron Firestein, Laura Corson, Alex Vanderbilt, Simon Williams, Anneleen Daemen, Marcia Belvin, Charles Eigenbrot, Peter K Jackson, Shiva Malek, Georgia Hatzivassiliou, Deepak Sampath, Marie Evangelista, Thomas O'Brien
Metabolic reprogramming in tumors represents a potential therapeutic target. Herein we used shRNA depletion and a novel lactate dehydrogenase (LDHA) inhibitor, GNE-140, to probe the role of LDHA in tumor growth in vitro and in vivo. In MIA PaCa-2 human pancreatic cells, LDHA inhibition rapidly affected global metabolism, although cell death only occurred after 2 d of continuous LDHA inhibition. Pancreatic cell lines that utilize oxidative phosphorylation (OXPHOS) rather than glycolysis were inherently resistant to GNE-140, but could be resensitized to GNE-140 with the OXPHOS inhibitor phenformin...
October 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27387758/early-changes-in-the-metabolic-profile-of-activated-cd8-t-cells
#17
Clemens Cammann, Alexander Rath, Udo Reichl, Holger Lingel, Monika Brunner-Weinzierl, Luca Simeoni, Burkhart Schraven, Jonathan A Lindquist
BACKGROUND: Antigenic stimulation of the T cell receptor (TCR) initiates a change from a resting state into an activated one, which ultimately results in proliferation and the acquisition of effector functions. To accomplish this task, T cells require dramatic changes in metabolism. Therefore, we investigated changes of metabolic intermediates indicating for crucial metabolic pathways reflecting the status of T cells. Moreover we analyzed possible regulatory molecules required for the initiation of the metabolic changes...
2016: BMC Cell Biology
https://www.readbyqxmd.com/read/27384996/prognostic-significance-and-function-of-the-vacuolar-h-atpase-subunit-v1e1-in-esophageal-squamous-cell-carcinoma
#18
Sung Wook Son, Seok-Hyung Kim, Eun-Yi Moon, Dong-Hoon Kim, Suhkneung Pyo, Sung Hee Um
Vacuolar H+-ATPase (V-ATPase), a hetero-multimeric ATP-driven proton pump has recently emerged as a critical regulator of mTOR-induced amino acid sensing for cell growth. Although dysregulated activity of cell growth regulators is often associated with cancer, the prognostic significance and metabolic roles of V-ATPase in esophageal cancer progression remain unclear. Here, we show that high levels of V-ATPase subunit V1E1 (V-ATPase V1E1) were significantly associated with shortened disease-free survival in patients with esophageal squamous cell carcinoma (ESCC)...
August 2, 2016: Oncotarget
https://www.readbyqxmd.com/read/27236753/development-of-a-model-describing-regulation-of-casein-synthesis-by-the-mammalian-target-of-rapamycin-mtor-signaling-pathway-in-response-to-insulin-amino-acids-and-acetate
#19
J J Castro, S I Arriola Apelo, J A D R N Appuhamy, M D Hanigan
To improve dietary protein use efficiency in lactating cows, mammary protein synthesis responses to AA, energy substrates, and hormones must be better understood. These entities exert their effects through stimulation of mRNA translation via control of initiation and elongation rates at the cellular level. A central protein kinase of this phenomenon is the mammalian target of rapamycin (mTOR), which transfers the nutritional and hormonal stimuli onto a series of proteins downstream through a cascade of phosphorylation reactions that ultimately affect protein synthesis...
August 2016: Journal of Dairy Science
https://www.readbyqxmd.com/read/27210058/metformin-in-combination-with-5-fluorouracil-suppresses-tumor-growth-by-inhibiting-the-warburg-effect-in-human-oral-squamous-cell-carcinoma
#20
Koji Harada, Tarannum Ferdous, Toyoko Harada, Yoshiya Ueyama
Cancer cells show enhanced glucose consumption and lactate production even in the presence of abundant oxygen, a phenomenon known as the Warburg effect, which is related to tumor proliferation, progression and drug-resistance in cancers. Hypoxia-inducible factor-1 (HIF-1) and several members of Phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway positively contribute to the Warburg effect, whereas AMP activated protein Kinase (AMPK) acts as a negative regulator...
July 2016: International Journal of Oncology
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