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https://www.readbyqxmd.com/read/28102310/coordinated-cell-motility-is-regulated-by-a-combination-of-lkb1-farnesylation-and-kinase-activity
#1
S Wilkinson, Y Hou, J T Zoine, J Saltz, C Zhang, Z Chen, L A D Cooper, A I Marcus
Cell motility requires the precise coordination of cell polarization, lamellipodia formation, adhesion, and force generation. LKB1 is a multi-functional serine/threonine kinase that associates with actin at the cellular leading edge of motile cells and suppresses FAK. We sought to understand how LKB1 coordinates these multiple events by systematically dissecting LKB1 protein domain function in combination with live cell imaging and computational approaches. We show that LKB1-actin colocalization is dependent upon LKB1 farnesylation leading to RhoA-ROCK-mediated stress fiber formation, but membrane dynamics is reliant on LKB1 kinase activity...
January 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28099846/cell-of-origin-links-histotype-spectrum-to-immune-microenvironment-diversity-in-non-small-cell-lung-cancer-driven-by-mutant-kras-and-loss-of-lkb1
#2
Ashwini S Nagaraj, Jenni Lahtela, Annabrita Hemmes, Teijo Pellinen, Sami Blom, Jennifer R Devlin, Kaisa Salmenkivi, Olli Kallioniemi, Mikko I Mäyränpää, Katja Närhi, Emmy W Verschuren
Lung cancers exhibit pronounced functional heterogeneity, confounding precision medicine. We studied how the cell of origin contributes to phenotypic heterogeneity following conditional expression of Kras(G12D) and loss of Lkb1 (Kras;Lkb1). Using progenitor cell-type-restricted adenoviral Cre to target cells expressing surfactant protein C (SPC) or club cell antigen 10 (CC10), we show that Ad5-CC10-Cre-infected mice exhibit a shorter latency compared with Ad5-SPC-Cre cohorts. We further demonstrate that CC10(+) cells are the predominant progenitors of adenosquamous carcinoma (ASC) tumors and give rise to a wider spectrum of histotypes that includes mucinous and acinar adenocarcinomas...
January 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/28087886/d-chiro-inositol-ameliorates-endothelial-dysfunction-via-inhibition-of-oxidative-stress-and-mitochondrial-fission
#3
Bobo Zhang, Xudan Guo, Yunlong Li, Qiang Peng, Jinfeng Gao, Baolin Liu, Min Wang
SCOPE: D-chiro inositol (DCI), an isomer of inositol, possesses anti-oxidative and endothelial protective properties. The mechanism by which DCI prevents endothelial dysfunction was investigated, with emphasis on oxidative stress. METHODS AND RESULTS: DCI was found to inhibit NOX4 induction and enhance Nrf2 activity in palmitate (PA)-stimulated cells, showing that DCI prevents oxidative stress. DCI suppressed Ser616 phosphorylation and increased Ser637 phosphorylation of Drp1 and inhibited PA-induced mitochondrial fission...
January 14, 2017: Molecular Nutrition & Food Research
https://www.readbyqxmd.com/read/28087810/akt1-lkb1-and-yap1-revealed-as-myc-interactors-with-nanoluc-based-protein-fragment-complementation-assay
#4
Xiu-Lei Mo, Qi Qi, Andrei A Ivanov, Qiankun Niu, Yin Luo, Jonathan Havel, Russell Goetze, Sydney Bell, Carlos S Moreno, Lee A D Cooper, Margaret A Johns, Fadlo R Khuri, Yuhong Du, Haian Fu
The c-Myc (MYC) transcription factor is a major cancer driver and a well-validated therapeutic target. However, directly targeting MYC has been challenging. Thus, identifying proteins that interact with and regulate MYC may provide alternative strategies to inhibit its oncogenic activity. Here we report the development of a NanoLuc®-based protein-fragment complementation assay (NanoPCA) and mapping of the MYC protein interaction hub in live mammalian cells. The NanoPCA system was configured to enable detection of protein-protein interactions (PPI) at the endogenous level, as shown with PRAS40 dimerization, and detection of weak interactions, such as PINCH1-NCK2...
January 13, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28071670/benzyl-isothiocyanate-potentiates-p53-signaling-and-antitumor-effects-against-breast-cancer-through-activation-of-p53-lkb1-and-p73-lkb1-axes
#5
Bei Xie, Arumugam Nagalingam, Panjamurthy Kuppusamy, Nethaji Muniraj, Peter Langford, Balázs Győrffy, Neeraj K Saxena, Dipali Sharma
Functional reactivation of p53 pathway, although arduous, can potentially provide a broad-based strategy for cancer therapy owing to frequent p53 inactivation in human cancer. Using a phosphoprotein-screening array, we found that Benzyl Isothiocynate, (BITC) increases p53 phosphorylation in breast cancer cells and reveal an important role of ERK and PRAS40/MDM2 in BITC-mediated p53 activation. We show that BITC rescues and activates p53-signaling network and inhibits growth of p53-mutant cells. Mechanistically, BITC induces p73 expression in p53-mutant cells, disrupts the interaction of p73 and mutant-p53, thereby releasing p73 from sequestration and allowing it to be transcriptionally active...
January 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28069811/tgf-%C3%AE-1-smad3-pathway-targets-pp2a-ampk-foxo1-to-regulate-hepatic-gluconeogenesis
#6
Hariom Yadav, Samir Devalaraja, Stephanie Chung, Sushil G Rane
Maintenance of glucose homeostasis is essential for normal physiology. Deviation from normal glucose levels, in either direction, increases susceptibility to serious medical complications such as hypoglycemia or diabetes. Maintenance of glucose homeostasis is achieved via functional interactions amongst various organs, liver, skeletal muscle, adipose tissue, brain and the endocrine pancreas. The liver is the primary site for endogenous glucose production, especially during states of prolonged fasting. However, enhanced gluconeogenesis is also a signature feature of type 2 diabetes (T2D)...
January 9, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28067405/lkb1-regulation-of-skeletal-muscle-development-metabolism-and-muscle-progenitor-cell-homeostasis
#7
REVIEW
Tizhong Shan, Ziye Xu, Jiaqi Liu, Weiche Wu, Yizhen Wang
Liver kinase B1 (Lkb1), also named as Serine/Threonine protein kinase 11 (STK11), is a serine/threonine kinase that plays crucial roles in various cellular processes including cell survival, cell division, cellular polarity, cell growth, cell differentiation, and cell metabolism. In metabolic tissues, Lkb1 regulates glucose homeostasis and energy metabolism through phosphorylating and activating the AMPK subfamily proteins. In skeletal muscle, Lkb1 affects muscle development and postnatal growth, lipid and fatty acid oxidation, glucose metabolism and insulin sensitivity...
January 9, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28045069/local-alignment-vectors-reveal-cancer-cell-induced-ecm-fiber-remodeling-dynamics
#8
Byoungkoo Lee, Jessica Konen, Scott Wilkinson, Adam I Marcus, Yi Jiang
Invasive cancer cells interact with the surrounding extracellular matrix (ECM), remodeling ECM fiber network structure by condensing, degrading, and aligning these fibers. We developed a novel local alignment vector analysis method to quantitatively measure collagen fiber alignment as a vector field using Circular Statistics. This method was applied to human non-small cell lung carcinoma (NSCLC) cell lines, embedded as spheroids in a collagen gel. Collagen remodeling was monitored using second harmonic generation imaging under normal conditions and when the LKB1-MARK1 pathway was disrupted through RNAi-based approaches...
January 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28034896/role-of-cps1-in-cell-growth-metabolism-and-prognosis-in-lkb1-inactivated-lung-adenocarcinoma
#9
Müge Çeliktaş, Ichidai Tanaka, Satyendra Chandra Tripathi, Johannes F Fahrmann, Clemente Aguilar-Bonavides, Pamela Villalobos, Oliver Delgado, Dilsher Dhillon, Jennifer B Dennison, Edwin J Ostrin, Hong Wang, Carmen Behrens, Kim-Anh Do, Adi F Gazdar, Samir M Hanash, Ayumu Taguchi
BACKGROUND: Liver kinase B1 (LKB1) is a tumor suppressor in lung adenocarcinoma (LADC). We investigated the proteomic profiles of 45 LADC cell lines with and without LKB1 inactivation. Carbamoyl phosphate synthetase 1 (CPS1), the first rate-limiting mitochondrial enzyme in the urea cycle, was distinctively overexpressed in LKB1-inactivated LADC cell lines. We therefore assessed the role of CPS1 and its clinical relevance in LKB1-inactivated LADC. METHODS: Mass spectrometric profiling of proteome and metabolome and function of CPS1 were analyzed in LADC cell lines...
March 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/28034771/lkb1-promotes-metabolic-flexibility-in-response-to-energy-stress
#10
Seth J Parker, Robert U Svensson, Ajit S Divakaruni, Austin E Lefebvre, Anne N Murphy, Reuben J Shaw, Christian M Metallo
The Liver Kinase B1 (LKB1) tumor suppressor acts as a metabolic energy sensor to regulate AMP-activated protein kinase (AMPK) signaling and is commonly mutated in various cancers, including non-small cell lung cancer (NSCLC). Tumor cells deficient in LKB1 may be uniquely sensitized to metabolic stresses, which may offer a therapeutic window in oncology. To address this question we have explored how functional LKB1 impacts the metabolism of NSCLC cells using (13)C metabolic flux analysis. Isogenic NSCLC cells expressing functional LKB1 exhibited higher flux through oxidative mitochondrial pathways compared to those deficient in LKB1...
December 26, 2016: Metabolic Engineering
https://www.readbyqxmd.com/read/28031112/-overexpression-of-liver-kinase-b1-inhibits-the-proliferation-of-lung-cancer-cells
#11
Yang Li, Libin Zhang, Ping Wang
Objective To explore the effect of overexpressed liver kinase B1(LKB1) on the proliferation of lung cancer cell lines. Methods The expression levels of LKB1 and PTEN in A549, NCI-H23, NCI-H157, XWLC-05, NCI-H446 lung cancer cells were detected by immunocytochemistry (ICC) and Western blotting. Plasmid pcDNA3.1(+)-LKB1 and empty vector pcDNA3.1(+)-null were separately transfected into the above five cell lines, and then the expression of LKB1 mRNA and protein were determined by quantitative real-time PCR and Western blotting, respectively...
January 2017: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
https://www.readbyqxmd.com/read/28012135/eicosapentaenoic-acid-enriched-phosphatidylcholine-attenuated-hepatic-steatosis-through-regulation-of-cholesterol-metabolism-in-rats-with-nonalcoholic-fatty-liver-disease
#12
Yanjun Liu, Di Shi, Yingying Tian, Yuntao Liu, Qiping Zhan, Jie Xu, Jingfeng Wang, Changhu Xue
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Disturbed cholesterol metabolism plays a crucial role in the development of NAFLD. The present study was conducted to evaluate the effects of EPA-PC extracted from sea cucumber on liver steatosis and cholesterol metabolism in NAFLD. Male Wistar rats were randomly divided into seven groups (normal control group, model group, lovastatin group, low- and high-dose EPA groups, and low- and high-dose EPA-PC groups). Model rats were established by administering a diet containing 1% orotic acid...
December 24, 2016: Lipids
https://www.readbyqxmd.com/read/27974177/serine-metabolism-links-tumor-suppression-to-the-epigenetic-landscape
#13
Xia Gao, Jason W Locasale
Intermediary metabolism provides substrates that shape epigenetic status, but whether this interaction can be responsible for oncogenesis is largely unknown. In a recent issue of Nature, Kottakis et al. (2016) now show that the common tumor suppressor gene LKB1 can function by mediating this connection through an LKB1/AMPK/mTOR signaling axis.
December 13, 2016: Cell Metabolism
https://www.readbyqxmd.com/read/27951515/polyphenolics-from-mango-mangifera-indica-l-suppress-breast-cancer-ductal-carcinoma-in-situ-proliferation-through-activation-of-ampk-pathway-and-suppression-of-mtor-in-athymic-nude-mice
#14
Matthew J Nemec, Hyemee Kim, Alexandria B Marciante, Ryan C Barnes, Erik D Hendrick, William H Bisson, Stephen T Talcott, Susanne U Mertens-Talcott
The objective of this study was to assess the underlying mechanisms of mango polyphenol decreased cell proliferation and tumor volume in ductal carcinoma in situ breast cancer. We hypothesized that mango polyphenols suppress signaling along the AKT/mTOR axis while up-regulating AMPK. To test this hypothesis, mango polyphenols (0.8 mg gallic acid equivalents per day) and pyrogallol (0.2 mg/day) were administered for 4 weeks to mice xenografted with MCF10DCIS.com cells subcutaneously (n=10 per group). Tumor volumes were significantly decreased, both mango and pyrogallol groups displayed greater than 50% decreased volume compared to control...
November 15, 2016: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/27916511/liqustri-lucidi-fructus-inhibits-hepatic-injury-and-functions-as-an-antioxidant-by-activation-of-amp-activated-protein-kinase-in%C3%A2-vivo-and-in%C3%A2-vitro
#15
Hye Lim Seo, Su Youn Baek, Eun Hye Lee, Ju-Hee Lee, Seul-Gi Lee, Kwang-Youn Kim, Mi Hee Jang, Min-Hui Park, Joung-Hee Kim, Keuk-Jun Kim, Hyeong Sik Lee, Soon-Cheol Ahn, Jong Rok Lee, Sook Jahr Park, Sang Chan Kim, Young Woo Kim
Medicinal herbs are used to treat or prevent various diseases, and function to regulate protective mechanisms as nutraceuticals. Fructus Ligustri lucidi is the fruit of Ligustrum lucidum and has been used for its tonic effects on the liver. This study was designed to examine the effects of Fructus Ligustri lucidi water extract (FLL) against severe oxidative stress and mitochondrial impairment in vivo and in vitro and to elucidate its cellular mechanisms of action. Treatment of HepG2 cells with arachidonic acid (AA) + iron successfully induced oxidative stress and apoptosis, as indicated by depletion of glutathione, formation of ROS, decreses in mitochondrial membrane potential (Δψm), and altered expression of apoptosis-related proteins, such as procaspase-3 and Bcl-xL...
January 25, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/27910069/lkb1-as-a-tumor-suppressor-in-uterine-cancer-mouse-models-and-translational-studies
#16
Christopher G Peña, Diego H Castrillón
The LKB1 tumor suppressor was identified in 1998 as the gene mutated in the Peutz-Jeghers Syndrome (PJS), a hereditary cancer predisposition characterized by gastrointestinal polyposis and a high incidence of cancers, particularly carcinomas, at a variety of anatomic sites including the gastrointestinal tract, lung, and female reproductive tract. Women with PJS have a high incidence of carcinomas of the uterine corpus (endometrium) and cervix. The LKB1 gene is also somatically mutated in human cancers arising at these sites...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/27908725/par3l-enhances-colorectal-cancer-cell-survival-by-inhibiting-lkb1-ampk-signaling-pathway
#17
Taiyuan Li, Dongning Liu, Xiong Lei, Qunguang Jiang
Partitioning defective 3-like protein (Par3L) is a recently identified cell polarity protein that plays an important role in mammary stem cell maintenance. Previously, we showed that high expression of Par3L is associated with poor survival in malignant colorectal cancer (CRC), but the underlying mechanism remained unknown. To this end, we established a Par3L knockout colorectal cancer cell line using the CRISPR/Cas system. Interestingly, reduced proliferation, enhanced cell death and caspase-3 activation were observed in Par3L knockout (KO) cells as compared with wildtype (WT) cells...
January 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27896618/loss-of-liver-kinase-b1-causes-planar-polarity-defects-in-cochlear-hair-cells-in-mice
#18
Yuqin Men, Aizhen Zhang, Liwen Zhang, Yecheng Jin, Zhishuo Wang, Jing Zhao, Xiaolin Yu, Jian Zhang, Jiangang Gao
The tumor suppressor gene liver kinase B1 (LKB1), also called STK11, encodes a serine/threonine kinase. LKB1 plays crucial roles in cell differentiation, proliferation, and polarity. In this study, LKB1 conditional knockout mice (LKB1(Pax2) CKO mice) were generated using Pax2-Cre mice to investigate the function of LKB1 in inner ear hair cells during early embryonic period. LKB1(Pax2) CKO mice died perinatally. Immunofluorescence and scanning electron microscopy revealed that stereociliary bundles in LKB1(Pax2) CKO mice were clustered and misoriented, respectively...
November 28, 2016: Frontiers of Medicine
https://www.readbyqxmd.com/read/27875786/inflammation-dysregulated-metabolism-and-aromatase-in-obesity-and-breast-cancer
#19
REVIEW
Heba Zahid, Evan R Simpson, Kristy A Brown
Obesity is associated with an increased risk of estrogen-dependent breast cancer after menopause. Adipose tissue undergoes important changes in obesity due to excess storage of lipids, leading to adipocyte cell death and the recruitment of macrophages. The resultant state of chronic low-grade inflammation is associated with the activation of NFkB signaling and elevated levels of aromatase, the rate-limiting enzyme in estrogen biosynthesis. This occurs not only in the visceral and subcutaneous fat, but also in the breast fat...
December 2016: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/27849007/two-ptp-receptors-mediate-cspg-inhibition-by-convergent-and-divergent-signaling-pathways-in-neurons
#20
Yosuke Ohtake, Daniella Wong, P M Abdul-Muneer, Michael E Selzer, Shuxin Li
Receptor protein tyrosine phosphatase σ (PTPσ) and its subfamily member LAR act as transmembrane receptors that mediate growth inhibition of chondroitin sulfate proteoglycans (CSPGs). Inhibition of either receptor increases axon growth into and beyond scar tissues after CNS injury. However, it is unclear why neurons express two similar CSPG receptors, nor whether they use the same or different intracellular pathways. We have now studied the signaling pathways of these two receptors using N2A cells and primary neurons derived from knockout mice...
November 16, 2016: Scientific Reports
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