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https://www.readbyqxmd.com/read/28915708/targeting-metabolism-and-amp-activated-kinase-with-metformin-to-sensitize-non-small-cell-lung-cancer-nsclc-to-cytotoxic-therapy-translational-biology-and-rationale-for-current-clinical-trials
#1
REVIEW
Michael Troncone, Stephanie M Cargnelli, Linda A Villani, Naghmeh Isfahanian, Lindsay A Broadfield, Laura Zychla, Jim Wright, Gregory Pond, Gregory R Steinberg, Theodoros Tsakiridis
Lung cancer is the most fatal malignancy worldwide, in part, due to high resistance to cytotoxic therapy. There is need for effective chemo-radio-sensitizers in lung cancer. In recent years, we began to understand the modulation of metabolism in cancer and its importance in tumor progression and survival after cytotoxic therapy. The activity of biosynthetic pathways, driven by the Growth Factor Receptor/Ras/PI3k/Akt/mTOR pathway, is balanced by the energy stress sensor pathway of LKB1/AMPK/p53. AMPK responds both to metabolic and genotoxic stress...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28903364/kif7-attenuates-prostate-tumor-growth-through-lkb1-mediated-akt-inhibition
#2
Kai Yau Wong, Jing Liu, Kwok Wah Chan
This study investigated kinesin family member 7 (KIF7) expression and function in prostate cancer (PCa). Our results showed that KIF7 was significantly downregulated in PCa, compared with normal, benign prostatic hyperplasia and prostate intraepithelial neoplasia tissues, partially through promoter hypermethylation. We further investigated the effects of KIF7 coiled coil (CC) domain and motor domain (MD) on PCa development in vitro and in vivo. Our results showed that KIF7-CC but not KIF7-MD significantly attenuated proliferation and colony formation, impeded migration and invasion, induced apoptosis and sensitized PCa cells to paclitaxel...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28895643/thyroid-hormone-induced-expression-of-the-hepatic-scaffold-proteins-sestrin2-%C3%AE-klotho-and-frs2%C3%AE-in-relation-to-fgf21-ampk-signaling
#3
Luis A Videla, Romina Vargas, Barbara Riquelme, Javier Fernández, Virginia Fernández
Thyroid hormone (3,3',5-triiodothyronine, T3) accelerates energy metabolism in the liver through mechanisms involving upregulation of AMP-activated protein kinase (AMPK). This study aims to assess the influence of T3 on the expression of the scaffold proteins β-Klotho, fibroblast growth factor receptor substrate 2α (FRS2α), and Sestrin2 in relation to FGF21-AMPK signaling. Male Sprague-Dawley rats were given 0.1 mg T3/kg or hormone vehicle (controls) and studies were done 24 h after treatment. These include measurements of the mRNA expression (qPCR) of hepatic β-Klotho, FGF21, FGF21 receptor-1 (FGFR1), extracellular-signal-regulated kinase 1/2 (ERK1/2), FRS2α, ribosomal S6 kinase-1 (RSK1), liver kinase B1 (LKB1), AMPK, and Sestrin2...
September 11, 2017: Experimental and Clinical Endocrinology & Diabetes
https://www.readbyqxmd.com/read/28882949/phe354leu-polymorphism-of-lkb1-is-a-potential-prognostic-factor-for-cytogenetically-normal-acute-myeloid-leukemia
#4
Ming-Yu Yang, Hui-Hua Hsiao, Yi-Chang Liu, Cheng-Ming Hsu, Sheng-Fung Lin, Pai-Mei Lin
BACKGROUND/AIM: Liver kinase B1 (LKB1) is a major activator of the AMP-dependent kinase/mammalian target of rapamycin pathway. The prevalence and the specificity of LKB1 gene mutation in acute myeloid leukemia (AML) have not been well established. This study aimed to examine mutation of LKB1 in AML and its clinical and pathological implications. PATIENTS AND METHODS: Eighty-five patients newly diagnosed with cytogenetically normal AML were analyzed using polymerase chain reaction followed by direct sequencing...
September 2017: In Vivo
https://www.readbyqxmd.com/read/28882900/adipocyte-liver-kinase-b1-suppresses-beige-adipocyte-renaissance-through-class-iia-histone-deacetylase-4
#5
Yangmeng Wang, Esther Paulo, Dongmei Wu, Yixuan Wu, Wendong Huang, Ajay Chawla, Biao Wang
Uncoupling protein 1(+) (UCP1(+)) beige adipocytes are dynamically regulated by environment in rodents and humans; cold induces formation of beige adipocytes, while warm temperature and nutrient excess lead to their disappearance. Beige adipocytes can form through de novo adipogenesis, however how "beigeing" characteristics are maintained afterwards is largely unknown. Here we show that beige adipocytes formed postnatally in subcutaneous inguinal white adipose tissue (iWAT) lost thermogenic gene expression and multilocular morphology at adult stage, but cold restored their "beigeing" characteristics, a phenomenon termed as beige adipocyte renaissance...
September 7, 2017: Diabetes
https://www.readbyqxmd.com/read/28847007/homeostatic-control-of-metabolic-and-functional-fitness-of-treg-cells-by-lkb1-signalling
#6
Kai Yang, Daniel Bastardo Blanco, Geoffrey Neale, Peter Vogel, Julian Avila, Clary B Clish, Chuan Wu, Sharad Shrestha, Sherri Rankin, Lingyun Long, Anil Kc, Hongbo Chi
Regulatory T cells (Treg cells) have a pivotal role in the establishment and maintenance of immunological self-tolerance and homeostasis. Transcriptional programming of regulatory mechanisms facilitates the functional activation of Treg cells in the prevention of diverse types of inflammatory responses. It remains unclear how Treg cells orchestrate their homeostasis and interplay with environmental signals. Here we show that liver kinase B1 (LKB1) programs the metabolic and functional fitness of Treg cells in the control of immune tolerance and homeostasis...
August 31, 2017: Nature
https://www.readbyqxmd.com/read/28837153/cardioprotective-effects-of-fibroblast-growth-factor-21-against-doxorubicin-induced-toxicity-via-the-sirt1-lkb1-ampk-pathway
#7
Shudong Wang, Yonggang Wang, Zhiguo Zhang, Quan Liu, Junlian Gu
Doxorubicin (DOX) is a highly effective antineoplastic anthracycline drug; however, the adverse effect of the cardiotoxicity has limited its widespread application. Fibroblast growth factor 21 (FGF21), as a well-known regulator of glucose and lipid metabolism, was recently shown to exert cardioprotective effects. The aim of this study was to investigate the possible protective effects of FGF21 against DOX-induced cardiomyopathy. We preliminarily established DOX-induced cardiotoxicity models in H9c2 cells, adult mouse cardiomyocytes, and 129S1/SyImJ mice, which clearly showed cardiac dysfunction and myocardial collagen accumulation accompanying by inflammatory, oxidative stress, and apoptotic damage...
August 24, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28827412/macrophage-liver-kinase-b1-inhibits-foam-cell-formation-and-atherosclerosis
#8
Zhaoyu Liu, Huaiping Zhu, Xaoyan Dai, Cheng Wang, Ye Ding, Ping Song, Ming-Hui Zou
Rationale: Liver kinase B1 (LKB1) is a serine/threonine kinase and tumor suppressor, which regulates the homeostasis of hematopoietic cells and immune responses. Macrophages transform into foam cells upon taking-in lipids. No role for LKB1 in foam cell formation has previously reported. Objective: We sought to establish the role of LKB1 in atherosclerotic foam cell formation. Methods and Results: LKB1 expression was examined in human carotid atherosclerotic plaques and in western diet fed atherosclerosis-prone Ldlr(-/-) and ApoE(-/-) mice...
August 21, 2017: Circulation Research
https://www.readbyqxmd.com/read/28817623/metformin-attenuates-myocardial-ischemia-reperfusion-injury-via-up-regulation-of-antioxidant-enzymes
#9
Xiaoling Wang, Lei Yang, Licheng Kang, Jing Li, Liang Yang, Jincai Zhang, Jie Liu, Mengmeng Zhu, Qiong Zhang, Yanna Shen, Zhi Qi
The objective was to examine the protective effect of metformin (Met) on myocardial ischemia-reperfusion (IR) injury and whether the mechanism was related to the AMPK/ antioxidant enzymes signaling pathway. Rat Langendorff test and H2O2-treated rat cardiomyocytes (H9c2) were used in this study. Met treatment significantly improved left ventricular (LV) function, reduced infarct size and CK-MB release in comparison with IR group. Decreased TUNEL staining positive cells were also observed in IR+Met group ex vivo...
2017: PloS One
https://www.readbyqxmd.com/read/28813465/long-term-persistent-infection-of-hpv-16-e6-up-regulate-sp1-and-htert-by-inhibiting-lkb1-in-lung-cancer-cells
#10
Jing-Hua Yang, Xiao-Yan Li, Xin Wang, Wei-Jian Hou, Xue-Shan Qiu, En-Hua Wang, Guang-Ping Wu
HPV 16 E6 upregulates hTERT expression in lung cancer cells. However, the underlying molecular mechanism is unclear. In this paper, E6, LKB1, SP1, and hTERT mRNA expression levels were detected in brushing cells of patients with lung cancer (n = 106) and with benign lung disease (n = 68) by qRT-PCR. The mRNA expression levels of E6, SP1, and hTERT were significantly increased in the malignant group compared with the benign group (P < 0.01). Conversely, the mRNA expression level of LKB1 was significantly decreased in the malignant group (P < 0...
2017: PloS One
https://www.readbyqxmd.com/read/28801289/-lkb1-regulates-epithelial-mesenchymal-transition-in-peutz-jeghers-hamartoma-and-intestinal-epithelial-cells
#11
Chao Zhong, Liang Peng, Ran Li, Jing Chen, Xin-Qi Chen, Di Zeng, Xiao-Ping Xu, Zhi-Qing Wang, Chu-di Chen, Ya-Dong Wang, Ai-Min Li, Si-de Liu, Bao-Ping Wu
OBJECTIVE: To investigate the molecular mechanism by which LKB1 regulates epithelial-mesenchymal transition (EMT) in Peutz-Jeghers hamartoma and intestinal epithelial cells. METHODS: Immunohistochemistry was used to detect gene expression of LKB1, E-cadherin, and vimentin in 20 hamartoma tissues and 10 normal intestinal tissues, and collagen fiber deposition was analyzed using Masson trichrome staining. Normal intestinal epithelial NCM460 cells were transfected with LKB1 shRNA plasmid or negative control via lentiviral vectors, and the role of LKB1 in cell polarization and migration were determined using CCK8 and Transwell assays...
August 20, 2017: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
https://www.readbyqxmd.com/read/28789977/ablation-of-systemic-sirt1-activity-promotes-nonalcoholic-fatty-liver-disease-by-affecting-liver-mesenteric-adipose-tissue-fatty-acid-mobilization
#12
Junrui Cheng, Chun Liu, Kangquan Hu, Andrew Greenberg, Dayong Wu, Lynne M Ausman, Michael W McBurney, Xiang-Dong Wang
Sirtuin 1 (SIRT1) has been reported to protect against nonalcoholic fatty liver disease (NAFLD) development. The mechanism of how SIRT1 deacetylase activity affects NAFLD has not been well investigated. The current investigation addressed the causal effect of systemic SIRT1 activity on NAFLD development and the underlying mechanism involved in both liver and mesenteric adipose tissue (MAT). Both SIRT1 homozygous mice ablated the catalytic activity (sirt1(Y/Y)) and their corresponding wild type littermates (WT) were fed a high fat diet (HFD, 60% calories from fat) for 34weeks...
August 5, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28767695/drosophila-lkb1-is-required-for-the-assembly-of-the-polarized-actin-structure-that-allows-spermatid-individualization
#13
Jean-Louis Couderc, Graziella Richard, Caroline Vachias, Vincent Mirouse
In mammals, a testis-specific isoform of the protein kinase LKB1 is required for spermiogenesis, but its exact function and specificity are not known. Human LKB1 rescues the functions of Drosophila Lkb1 essential for viability, but these males are sterile, revealing a new function for this genes in fly. We also identified a testis-specific transcript generated by an alternative promoter and that only differs by a longer 5'UTR. We show that dLKB1 is required in the germline for the formation of the actin cone, the polarized structure that allows spermatid individualization and cytoplasm excess extrusion during spermiogenesis...
2017: PloS One
https://www.readbyqxmd.com/read/28766983/lkb1-ampk-modulates-nutrient-induced-changes-in-the-mode-of-division-of-intestinal-epithelial-crypt-cells-in-mice
#14
Katherine Blackmore, Weinan Zhou, Megan J Dailey
Nutrient availability influences intestinal epithelial stem cell proliferation and tissue growth. Increases in food result in a greater number of epithelial cells, villi height and crypt depth. We investigated whether this nutrient-driven expansion of the tissue is the result of a change in the mode of intestinal epithelial stem cell division and if LKB1-AMPK signaling plays a role. We utilized in vivo and in vitro experiments to test this hypothesis. C57BL/6J mice were separated into four groups and fed varying amounts of chow for 18 h: (1) ad libitum, (2) 50% of their average daily intake (3) fasted or (4) fasted for 12 h and refed...
January 1, 2017: Experimental Biology and Medicine
https://www.readbyqxmd.com/read/28766947/creatine-monohydrate-enhances-energy-status-and-reduces-glycolysis-via-inhibition-of-ampk-pathway-in-pectoralis-major-muscle-of-transport-stressed-broilers
#15
Lin Zhang, Xiaofei Wang, Jiaolong Li, Xudong Zhu, Feng Gao, Guanghong Zhou
Creatine monohydrate (CMH) contributes to reduce transport-induced muscle rapid glycolysis and improve meat quality of broilers, but the underlying mechanism is still unknown. Therefore, this study aimed to investigate the molecular mechanisms underlying the ameliorative effects of CMH on muscle glycolysis metabolism of transported broilers during summer. The results showed that 3 h transport during summer elevated chicken live weight loss and plasma corticosterone concentration; decreased muscle concentrations of ATP, creatine, and energy charge value; increased muscle AMP concentration and AMP/ATP ratio; and upregulated muscle mRNA expression of LKB1 and AMPKα2, as well as protein expression of p-LKB1(Thr189) and p-AMPKα(Thr172), which subsequently resulted in rapid glycolysis in the pectoralis major muscle and consequent reduction of meat quality...
August 16, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/28761738/results-of-the-safety-run-in-part-of-the-metal-metformin-in-advanced-lung-cancer-study-a-multicentre-open-label-phase-i-ii-study-of-metformin-with-erlotinib-in-second-line-therapy-of-patients-with-stage-iv-non-small-cell-lung-cancer
#16
Floriana Morgillo, Morena Fasano, Carminia Maria Della Corte, Ferdinando Carlo Sasso, Federica Papaccio, Giuseppe Viscardi, Giovanna Esposito, Raimondo Di Liello, Nicola Normanno, Annalisa Capuano, Liberato Berrino, Giovanni Vicidomini, Alfonso Fiorelli, Mario Santini, Fortunato Ciardiello
PURPOSE: Our previous works demonstrated the ability of metformin to revert resistance to gefitinib, a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in non-small-cell lung cancer (NSCLC) EGFR/LKB1 wild-type (WT) cell lines. However, the optimal dose of metformin to be used in non-diabetic patients still remains to be defined. The phase I-II trial METformin in Advanced Lung cancer (METAL) was designed to identify the maximum tolerated dose and to evaluate safety and activity of metformin combined with erlotinib in second-line treatment of patients with stage IV NSCLC, whose tumours harbour the WT EGFR gene...
2017: ESMO Open
https://www.readbyqxmd.com/read/28754670/gemcitabine-and-chk1-inhibitor-azd7762-synergistically-suppress-the-growth-of-lkb1-deficient-lung-adenocarcinoma
#17
Yan Liu, Yuyang Li, Xiaoen Wang, Feiyang Liu, Peng Gao, Max M Quinn, Fei Li, Ashley A Merlino, Cyril Benes, Qingsong Liu, Nathanael S Gray, Kwok-Kin Wong
Cells lacking the tumor suppressor gene LKB1/STK11 alter their metabolism to match the demands of accelerated growth, leaving them highly vulnerable to stress. However, targeted therapy for LKB1-deficient cancers has yet to be reported. In both Kras/p53/Lkb1 cell lines and a genetically engineered mouse model of Kras/p53/Lkb1-induced lung cancer, much higher rates of DNA damage occur, resulting in increased dependence on Chk1 checkpoint function. Here we demonstrate that short-term treatment with the Chk1 inhibitor AZD7762 reduces metabolism in pembrolizumab tumors, synergizing with the DNA-damaging drug gemcitabine to reduce tumor size in these models...
September 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28743498/hydrogen-rich-medium-protects-mouse-embryonic-fibroblasts-from-oxidative-stress-by-activating-lkb1-ampk-foxo1-signal-pathway
#18
Jihyun Lee, Goowon Yang, Young-Joo Kim, Quynh Hoa Tran, Wonchae Choe, Insug Kang, Sung Soo Kim, Joohun Ha
Persistent oxidative stress is recognized as a major cause of many pathological conditions as well as ageing. However, most clinical trials of dietary antioxidants have failed to produce successful outcomes in treating oxidative stress-induced diseases. Molecular hydrogen (H2) has recently received considerable attention as a therapeutic agent owing to its novel antioxidant properties, a selective scavenger of hydroxyl and peroxynitrite radicals. Beyond this, numerous reports support that H2 can modulate the activity of various cellular signal pathways...
September 23, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28736255/isoalantolactone-derivative-promotes-glucose-utilization-in-skeletal-muscle-cells-and-increases-energy-expenditure-in-db-db-mice-via-activating-ampk-dependent-signaling
#19
Deepti Arha, E Ramakrishna, Anand P Gupta, Amit K Rai, Aditya Sharma, Ishbal Ahmad, Mohammed Riyazuddin, Jiaur R Gayen, Rakesh Maurya, Akhilesh K Tamrakar
Augmenting glucose utilization and energy expenditure in skeletal muscle via AMP-activated protein kinase (AMPK) is an imperative mechanism for the management of type 2 diabetes. Chemical derivatives (2a-2h, 3, 4a-4d, 5) of the isoalantolactone (K007), a bioactive molecule from roots of Inula racemosa were synthesized to optimize the bioactivity profile to stimulate glucose utilization in skeletal muscle cells. Interestingly, 4a augmented glucose uptake, driven by enhanced translocation of glucose transporter 4 (GLUT4) to cell periphery in L6 rat skeletal muscle cells...
July 20, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28732195/fake-inhibitors-ampk-activation-trumps-inhibition
#20
Christopher G Langendorf, John W Scott, Bruce E Kemp
Protein kinase inhibitors have become increasingly important therapeutic drugs for the treatment of human diseases; however, resistance and off-target effects can limit their use. In this issue of Cell Chemical Biology, Ross et al. (2017) reveal a novel off-target mechanism where the Src kinase inhibitor SU6656 paradoxically primes AMPK for phosphorylation and activation by the upstream kinase LKB1.
July 20, 2017: Cell Chemical Biology
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