Browsing by Author "Kim, Jung-whan"
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Item Characterization of Squamous Cell Carcinomas During High and Low Glucose Treatments(2019-12) Gerold, Haleigh; Kim, Jung-whanLung squamous cell carcinoma (LSqCC) is one of the many subtypes of lung cancer, the first leading cause of cancer-related deaths in the United States. Despite many years of research effort, not much has been accomplished as far as improving treatment and patient 5-year survival rates for lung cancer. Through metabolic analysis, much research has been published describing LSqCC and squamous carcinoma cells (SqCC), in general, that describes potentially targetable phenotypes. Research published out of our lab showed LSqCC is highly dependent on glucose for survival, a targetable observation. In addition, results implicated transcription factors p63 and SOX2 are important for glucose uptake. Here, I perform a brief study of SqCC regarding the effect of the TAp63 protein isoform on glucose addiction and their ability to adapt to low glucose environments. This study reveals the non-importance of TAp63 in glucose uptake. Moreover, I demonstrate the ability for multiple SqCC to adapt and survive in low glucose environments. In addition, I provide preliminary insight into differential protein expression of low glucose adapted cells based on proteins previously studied in our lab. In summary, this study provides further insight into the upregulated glycolytic flux seen in SqCCs.Item The Distinct Metabolic Phenotype of Lung Squamous Cell Carcinoma Defines Selective Vulnerability to Glycolytic Inhibition(Springer Nature, 2018-08-20) Goodwin, Justin; Neugent, Michael L.; Lee, Shin Yup; Choe, Joshua H.; Choi, Hyunsung; Jenkins, Dana M. R.; Ruthenborg, Robin J.; Robinson, Maddox W.; Jeong, Ji Yun; Wake, Masaki; Abe, Hajime; Takeda, Norihiko; Endo, Hiroko; Inoue, Masahiro; Xuan, Zhenyu; Yoo, Hyuntae; Chen, Min; Ahn, Jung-Mo; Xuan, Zhenyu; Yoo, Hyuntae; Chen, Min; Ahn, Jung-Mo; Minna, John D.; Helke, Kristi L.; Singh, Pankaj K.; Shackelford, David B.; Kim, Jung-whan; Goodwin, Justin; Neugent, Michael L.; Lee, Shin Yup; Choe, Joshua H.; Choi, Hyunsung; Jenkins, Dana M. R.; Ruthenborg, Robin J.; Robinson, Maddox W.; Xuan, Zhenyu; Yoo, Hyuntae; Kim, Jung-whanAdenocarcinoma (ADC) and squamous cell carcinoma (SqCC) are the two predominant subtypes of non-small cell lung cancer (NSCLC) and are distinct in their histological, molecular and clinical presentation. However, metabolic signatures specific to individual NSCLC subtypes remain unknown. Here, we perform an integrative analysis of human NSCLC tumour samples, patient-derived xenografts, murine model of NSCLC, NSCLC cell lines and The Cancer Genome Atlas (TCGA) and reveal a markedly elevated expression of the GLUT1 glucose transporter in lung SqCC, which augments glucose uptake and glycolytic flux. We show that a critical reliance on glycolysis renders lung SqCC vulnerable to glycolytic inhibition, while lung ADC exhibits significant glucose independence. Clinically, elevated GLUT1-mediated glycolysis in lung SqCC strongly correlates with high F-18-FDG uptake and poor prognosis. This previously undescribed metabolic heterogeneity of NSCLC subtypes implicates significant potential for the development of diagnostic, prognostic and targeted therapeutic strategies for lung SqCC, a cancer for which existing therapeutic options are clinically insufficient.Item A Measurement of the Calorimeter Response to Single Hadrons and Determination of the Jet Energy Scale Uncertainty Using LHC Run-1 PP-Collision Data with the ATLAS Detector(Nature Publishing Group, 2016-05-18) Semba, H.; Takeda, N.; Isagawa, T.; Sugiura, Y.; Honda, K.; Wake, M.; Miyazawa, H.; Jenkins, Dana M. R.; Choi, Hyunsung; Kim, Jung-whan; http://dx.doi.org/10.1038/ncomms11635 (Kim, J-W); Jenkins, Dana M. R.; Choi, Hyunsung; Kim, Jung-whanIn severely hypoxic condition, HIF-1α-mediated induction of Pdk1 was found to regulate glucose oxidation by preventing the entry of pyruvate into the tricarboxylic cycle. Monocyte-derived macrophages, however, encounter a gradual decrease in oxygen availability during its migration process in inflammatory areas. Here we show that HIF-1α-PDK1-mediated metabolic changes occur in mild hypoxia, where mitochondrial cytochrome c oxidase activity is unimpaired, suggesting a mode of glycolytic reprogramming. In primary macrophages, PKM2, a glycolytic enzyme responsible for glycolytic ATP synthesis localizes in filopodia and lammelipodia, where ATP is rapidly consumed during actin remodelling processes. Remarkably, inhibition of glycolytic reprogramming with dichloroacetate significantly impairs macrophage migration in vitro and in vivo. Furthermore, inhibition of the macrophage HIF-1α-PDK1 axis suppresses systemic inflammation, suggesting a potential therapeutic approach for regulating inflammatory processes. Our findings thus demonstrate that adaptive responses in glucose metabolism contribute to macrophage migratory activity.Item A New Perspective on the Heterogeneity of Cancer Glycolysis(2018-10-22) Neugent, Michael L.; Goodwin, Justin; Sankaranarayanan, Ishwarya; Yetkin, Celal Emre; Hsieh, Meng-Hsiung; Kim, Jung-whan; Neugent, Michael L.; Sankaranarayanan, Ishwarya; Yetkin, Celal Emre; Hsieh, Meng-Hsiung; Kim, Jung-whanTumors are dynamic metabolic systems which highly augmented metabolic fluxes and nutrient needs to support cellular proliferation and physiological function. For many years, a central hallmark of tumor metabolism has emphasized a uniformly elevated aerobic glycolysis as a critical feature of tumorigenecity. This led to extensive efforts of targeting glycolysis in human cancers. However, clinical attempts to target glycolysis and glucose metabolism have proven to be challenging. Recent advancements revealing a high degree of metabolic heterogeneity and plasticity embedded among various human cancers may paint a new picture of metabolic targeting for cancer therapies with a renewed interest in glucose metabolism. In this review, we will discuss diverse oncogenic and molecular alterations that drive distinct and heterogeneous glucose metabolism in cancers. We will also discuss a new perspective on how aberrantly altered glycolysis in response to oncogenic signaling is further influenced and remodeled by dynamic metabolic interaction with surrounding tumor-associated stromal cells.Item Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype(Frontiers Media S.A., 2019-05-07) Min, B. -K; Park, S.; Kang, H. -J; Kim, D. W.; Ham, H. J.; Ha, C. -M; Choi, B. -J; Kim, Jung-whan; 0000-0002-7829-1480 (Kim, J-w); Kim, Jung-whanMetabolic reprogramming during macrophage polarization supports the effector functions of these cells in health and disease. Here, we demonstrate that pyruvate dehydrogenase kinase (PDK), which inhibits the pyruvate dehydrogenase-mediated conversion of cytosolic pyruvate to mitochondrial acetyl-CoA, functions as a metabolic checkpoint in M1 macrophages. Polarization was not prevented by PDK2 or PDK4 deletion but was fully prevented by the combined deletion of PDK2 and PDK4; this lack of polarization was correlated with improved mitochondrial respiration and rewiring of metabolic breaks that are characterized by increased glycolytic intermediates and reduced metabolites in the TCA cycle. Genetic deletion or pharmacological inhibition of PDK2/4 prevents polarization of macrophages to the M1 phenotype in response to inflammatory stimuli (lipopolysaccharide plus IFN-γ). Transplantation of PDK2/4-deficient bone marrow into irradiated wild-type mice to produce mice with PDK2/4-deficient myeloid cells prevented M1 polarization, reduced obesity-associated insulin resistance, and ameliorated adipose tissue inflammation. A novel, pharmacological PDK inhibitor, KPLH1130, improved high-fat diet-induced insulin resistance; this was correlated with a reduction in the levels of pro-inflammatory markers and improved mitochondrial function. These studies identify PDK2/4 as a metabolic checkpoint for M1 phenotype polarization of macrophages, which could potentially be exploited as a novel therapeutic target for obesity-associated metabolic disorders and other inflammatory conditions.Item Regulation of Acetate Utilization by Monocarboxylate Transporter 1 (MCT1) in Hepatocellular Carcinoma (HCC)(Cognizant Communication Corporation, 2018-10-22) Jeon, J. Y.; Lee, M.; Whang, S. H.; Kim, Jung-whan; Cho, A.; Yun, M.; 0000-0002-7829-1480 (Kim, J-w); Kim, Jung-whanAltered energy metabolism is a biochemical fingerprint of cancer cells. Hepatocellular carcinoma (HCC) shows reciprocal [¹⁸F]fluorodeoxyglucose (FDG) and [¹¹C]acetate uptake, as revealed by positron emission tomography/computed tomography (PET/CT). Previous studies have focused on the role of FDG uptake in cancer cells. In this study, we evaluated the mechanism and roles of [¹¹C]acetate uptake in human HCCs and cell lines. The expression of monocarboxylate transporters (MCTs) was assessed to determine the transporters of [¹¹C]acetate uptake in HCC cell lines and human HCCs with different [¹¹C]acetate uptake. Using two representative cell lines with widely different [¹¹C]acetate uptake (HepG2 for high uptake and Hep3B for low uptake), changes in [¹¹C]acetate uptake were measured after treatment with an MCT1 inhibitor or MCT1- targeted siRNA. To verify the roles of MCT1 in cells, oxygen consumption rate and the amount of lipid synthesis were measured. HepG2 cells with high [¹¹C]acetate uptake showed higher MCT1 expression than other HCC cell lines with low [¹¹C]acetate uptake. MCT1 expression was elevated in human HCCs with high [¹¹C] acetate uptake compared to those with low [¹¹C]acetate uptake. After blocking MCT1 with AR-C155858 or MCT1 knockdown, [¹¹C]acetate uptake in HepG2 cells was significantly reduced. Additionally, inhibition of MCT1 suppressed mitochondrial oxidative phosphorylation, lipid synthesis, and cellular proliferation in HCC cells with high [¹¹C]acetate uptake. MCT1 may be a new therapeutic target for acetate-dependent HCCs with high [¹¹C]acetate uptake, which can be selected by [¹¹C]acetate PET/CT imaging in clinical practice.Item Spatial Angular Compounding Technique for H-Scan Ultrasound Imaging.(2018-10-22) Khairalseed, Mawia; Xiong, Fangyuan; Kim, Jung-whan; Mattrey, Robert F.; Parker, Kevin J.; Hoyt, Kenneth; Khairalseed, Mawia; Xiong, Fangyuan; Kim, Jung-whan; Hoyt, KennethH-Scan is a new ultrasound imaging technique that relies on matching a model of pulse-echo formation to the mathematics of a class of Gaussian-weighted Hermite polynomials. This technique may be beneficial in the measurement of relative scatterer sizes and in cancer therapy, particularly for early response to drug treatment. Because current H-scan techniques use focused ultrasound data acquisitions, spatial resolution degrades away from the focal region and inherently affects relative scatterer size estimation. Although the resolution of ultrasound plane wave imaging can be inferior to that of traditional focused ultrasound approaches, the former exhibits a homogeneous spatial resolution throughout the image plane. The purpose of this study was to implement H-scan using plane wave imaging and investigate the impact of spatial angular compounding on H-scan image quality. Parallel convolution filters using two different Gaussian-weighted Hermite polynomials that describe ultrasound scattering events are applied to the radiofrequency data. The H-scan processing is done on each radiofrequency image plane before averaging to get the angular compounded image. The relative strength from each convolution is color-coded to represent relative scatterer size. Given results from a series of phantom materials, H-scan imaging with spatial angular compounding more accurately reflects the true scatterer size caused by reductions in the system point spread function and improved signal-to-noise ratio. Preliminary in vivo H-scan imaging of tumor-bearing animals suggests this modality may be useful for monitoring early response to chemotherapeutic treatment. Overall, H-scan imaging using ultrasound plane waves and spatial angular compounding is a promising approach for visualizing the relative size and distribution of acoustic scattering sources.