DOCSLIB.ORG

Targeting Hypoxia, HIF-1, and Tumor Glucose Metabolism to Improve Radiotherapy Efficacy

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Targeting Hypoxia, HIF-1, and Tumor Glucose Metabolism to Improve Radiotherapy Efficacy CCR FOCUS Targeting Hypoxia, HIF-1, and Tumor Glucose Metabolism to Improve Radiotherapy Efficacy Tineke W.H. Meijer, Johannes H.A.M. Kaanders, Paul N. Span, and Johan Bussink Abstract Radiotherapy, an important treatment modality in oncology, kills cells through induction of oxidative stress. However, malignant tumors vary in their response to irradiation as a consequence of resistance mechanisms taking place at the molecular level. It is important to understand these mechanisms of radioresistance, as counteracting them may improve the efficacy of radiotherapy. In this review, we describe how the hypoxia-inducible factor 1 (HIF-1) pathway has a profound effect on the response to radiotherapy. The main focus will be on HIF-1–controlled protection of the vasculature postirradiation and on HIF-1 regulation of glycolysis and the pentose phosphate pathway. This aberrant cellular metabolism increases the antioxidant capacity of tumors, thereby countering the oxidative stress caused by irradiation. From the results of translational studies and the first clinical phase I/II trials, it can be concluded that targeting HIF-1 and tumor glucose metabolism at several levels reduces the antioxidant capacity of tumors, affects the tumor microenvironment, and sensitizes various solid tumors to irradiation. Clin Cancer Res; 18(20); 5585–94. Ó2012 AACR. Introduction The hypoxia-inducible factor 1 (HIF-1) pathway enables When ionizing radiation is absorbed in tissue, free radi- tumor cells to survive by changing glucose metabolism cals are produced as a result of ionizations either directly in toward a glycolytic phenotype, by inducing angiogenesis the DNA molecule itself or indirectly in other cellular and by regulating pH balance and proliferation rate. This review describes how the HIF-1 pathway impacts on molecules, primarily water (H2O). This indirect effect leads to the production of reactive oxygen species (ROS), which radioresistance of solid tumors, with special focus on are molecules that contain chemically active oxygen mole- HIF-1–induced changes in tumor glucose metabolism. Fur- cules including superoxide radical anions and hydroxyl thermore, inhibition of HIF-1 and glucose metabolism is radicals, thereby inducing oxidative stress. ROS can diffuse discussed as a new method to overcome radioresistance. to the DNA to produce similar free radicals. These free radicals, whether they are produced as a result of the direct HIF-1 Pathway or indirect mechanism, break chemical bonds and initiate Hypoxia-inducible factor 1 the chain of events that results in DNA damage. Oxygen HIF-1 is a heterodimeric protein consisting of an O2- molecules are able to react with the free radicals to yield a regulated HIF-1a and a constitutively expressed HIF-1b stable change in the chemical composition of the DNA subunit. Under normoxia, HIF-1a is rapidly degraded, damage. In this way, oxygen chemically "fixes" DNA dam- whereas hypoxia leads to stabilization and accumulation age and this is the basic mechanism for the therapeutic use of HIF-1a (Figs. 1 and 2A and B; refs. 7 and 8). However, of ionizing radiation in cancer (1). Hypoxia, a pathophys- under certain normoxic conditions, HIF-1a expression can iologic characteristic of solid malignancies (Fig. 1), inter- be increased; for example, mutations in the von Hippel- feres with the fixation of DNA damage and is therefore a Lindau protein stabilize HIF-1a protein and PI3K/AKT/ major cause of resistance to irradiation (2–5). A number of mTOR activity stimulates translation of HIF-1a mRNA therapeutic approaches have been designed to overcome (7–11). Moreover, reactive oxygen and nitrogen species tumor hypoxia (2, 4, 6). inhibit proteasomal degradation of HIF-1a (10, 12). After stabilization of HIF-1a, the heterodimeric protein activates transcription of numerous genes involved in angiogenesis, proliferation, glycolytic tumor metabolism, and pH regu- Authors' Affiliation: Department of Radiation Oncology, Radboud Uni- lation (refs. 7, 10, and 13; Fig. 2B). versity Nijmegen Medical Centre, Nijmegen, The Netherlands Corresponding Author: Johan Bussink, Department of Radiation Oncol- ogy, 874, Radboud University Nijmegen Medical Centre, P.O. Box 9101, Glycolytic cancer cell metabolism and aggressive tumor 6500 HB Nijmegen, The Netherlands. Phone: 31-243-614-515; Fax: 31- behavior 243-610-792; E-mail: [email protected] Under aerobic conditions, normal cells generate energy doi: 10.1158/1078-0432.CCR-12-0858 by processing glucose both via inefficient glycolysis and Ó2012 American Association for Cancer Research. via more efficient mitochondrial oxidation. As hypoxia www.aacrjournals.org 5585 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2012 American Association for Cancer Research. CCR FOCUS decreases the rate of mitochondrial oxidation, tumor cells switch to glycolysis for energy production under hypoxic N circumstances (14). This process in which pyruvate, lactate, and hydrogen ions are produced is called anaerobic glycol- ysis or Pasteur effect (9, 15). However, a hallmark of cancer cells is a high rate of glucose consumption and lactate generation even in the presence of oxygen (aerobic glycol- ysis or Warburg effect; refs. 9, and 16–18). HIF-1 initiates transcription of genes that encode trans- porters and enzymes regulating glycolysis and the pentose phosphate pathway (Fig. 3; refs. 8 and 19). The glycolytic products pyruvate and lactate induce HIF-1a accumula- tion (20, 21), suggesting a feed-forward mechanism in N which HIF-1 causes a glycolytic metabolism with elevated pyruvate/lactate concentrations, which in turn increase © 2012 American Association for Cancer Research HIF-1 activity (Fig. 2B; refs. 19 and 22). Besides HIF-1, activated oncogenes (e.g., RAS and MYC)andthePI3K/ AKT/mTOR pathway are involved in the regulation of the metabolic shift to (aerobic) glycolysis (9, 16, 18). Figure 1. Immunofluorescent image of a human head and neck squamous cell carcinoma xenograft tumor (SCCNij172) showing HIF-1a expression The glycolytic switch may seem counterintuitive, given in hypoxic regions as assessed by pimonidazole staining. Red, HIF-1a; the less efficient energy production by glycolysis com- green, pimonidazole; white, vessels; N, necrosis. Magnification 100Â. pared with mitochondrial oxidation. However, the m Scale bar represents 100 m. glycolytic intermediate glucose-6-phosphate is also used A HIF-1α degradation under B Stabilization and activation of HIF-1 normoxia Growth factor Mutations: HIF-1α Physiological stress: stimulation: VHL - Hypoxia → Hydroxylation EGFR - Oxygen and PI3K/AKT/mTOR by nitrogen species prolyl hydroxylase activity HIF-1α OH α Binding of HIF-1 VHL protein accumulation α HIF-1 OH HIF-1α β VHL HIF-1 Cytoplasm Nucleus HIF-1α Degradation HIF-1β HRE DNA pH Proliferation regulation Angiogenesis Glycolysis producing pyruvate and lactate © 2012 American Association for Cancer Research CCR Focus Figure 2. Schematic representation of the HIF-1 pathway. A, under normoxic conditions, HIF-1a is rapidly degraded because of hydroxylation of HIF-1a by prolyl hydroxylase and subsequent binding of the von Hippel-Lindau protein. B, physiologic stress (hypoxia and reactive oxygen and nitrogen species), mutations in the von Hippel-Lindau protein and PI3K/AKT/mTOR activity contribute to HIF-1a stabilization and accumulation. Upon stabilization of HIF-1a,itbindstoHIF-1b. This HIF-1 complex binds to the hypoxia responsive element (HRE) of the DNA, thereby initiating the transcription of its target genes. This results in a glycolytic tumor metabolism among others. The glycolytic end products pyruvate and lactate induce HIF-1a accumulation, which in turn increases HIF-1 activity. AKT, protein kinase B; EGFR, epidermal growth factor receptor; HIF-1, hypoxia-inducible factor 1; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol-3-kinase;VHL,vonHippel-Lindauprotein. 5586 Clin Cancer Res; 18(20) October 15, 2012 Clinical Cancer Research Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2012 American Association for Cancer Research. HIF-1, Glucose Metabolism, and Resistance to Radiotherapy Glucose Glucose + H HCO3- GLUT3 GLUT1 + CAIX H Fibroblast Metalloproteinase NHE1 H2O CO2 Glycolysis Hyaluronidase Glucose H+ Degradation of HK H O + NADP+ NADPH 2 H extracellular H+ matrix and Glucose-6-P 6-P-gluconolactone 6-P-gluconate tumor-cell G6PD NADP+ migration Pentose Fructose-6-P phosphate shunt NADPH H+ Fructose-1,6-P 2 CO2 CO2 Erythrose-4-phosphate Glyceraldehyde-3-P TKL/TAL Ribose-5-phosphate Nucleotide and amino acid synthesis TCA Pyruvate required for proliferation Immune PDH LDHA escape ROS and free PDK1 Lactate radical Radioresistance scavenging Immune cell Metalloproteinase MCT4 Hyaluronidase Lactate Fibroblast Angiogenesis VEGF Endothelial cell © 2012 American Association for Cancer Research CCR Focus Figure 3. Tumor glucose metabolism and aggressive tumor behavior. HIF-1 activates transcription of transporters and enzymes regulating glycolysis and the pentose phosphate shunt. These transporters and enzymes are involved in glucose delivery into the cell (GLUT1 and GLUT3), phosphorylation of glucose to form glucose-6-phosphate (HK), conversion of glucose-6-phosphate into 6-phosphogluconolactone to support the pentose phosphate shunt (G6PD), conversion of pyruvate into lactate (LDHA), lactate transport (MCT4), and pH regulation (CAIX, NHE1). Furthermore, activation of PDK1 by HIF-1 inhibits the conversion of pyruvate to acetyl CoA, which results
Load more

Recommended publications
  • The Roles of Hypoxia-Inducible Factors and Non-Coding Rnas in Gastrointestinal Cancer
    G C A T T A C G G C A T genes Review The Roles of Hypoxia-Inducible Factors and Non-Coding RNAs in Gastrointestinal Cancer 1, 1, 2, 1, Hyun-Soo Cho y , Tae-Su Han y, Keun Hur * and Hyun Seung Ban * 1 Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea; [email protected] (H.-S.C.); [email protected] (T.H.) 2 Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu 41944, Korea * Correspondence: [email protected] (K.H.); [email protected] (H.S.B.); Tel.: +82-53-420-4821 (K.H.); +82-42-879-8176 (H.S.B.) These authors contributed equally to this work. y Received: 10 November 2019; Accepted: 2 December 2019; Published: 4 December 2019 Abstract: Hypoxia-inducible factors (HIFs) are transcription factors that play central roles in cellular responses against hypoxia. In most cancers, HIFs are closely associated with tumorigenesis by regulating cell survival, angiogenesis, metastasis, and adaptation to the hypoxic tumor microenvironment. Recently, non-coding RNAs (ncRNAs) have been reported to play critical roles in the hypoxic response in various cancers. Here, we review the roles of hypoxia-response ncRNAs in gastrointestinal cancer, with a particular focus on microRNAs and long ncRNAs, and discuss the functional relationships and regulatory mechanisms between HIFs and ncRNAs. Keywords: hypoxia; non-coding RNA; microRNA; hypoxia-inducible factor; gastrointestinal cancer 1. Introduction Gastrointestinal (GI) cancer is the most common type of cancer and second leading cause of cancer-related death [1]. GI cancer is particularly difficult to treat since it is usually found in an advanced stage.
    [Show full text]
  • Structural Comparison of GLUT1 to GLUT3 Reveal Transport Regulation Mechanism in Sugar Porter Family
    Published Online: 3 February, 2021 | Supp Info: http://doi.org/10.26508/lsa.202000858 Downloaded from life-science-alliance.org on 24 September, 2021 Research Article Structural comparison of GLUT1 to GLUT3 reveal transport regulation mechanism in sugar porter family Taniaˆ Filipa Custódio1,*, Peter Aasted Paulsen1,*, Kelly May Frain1, Bjørn Panyella Pedersen1,2 The human glucose transporters GLUT1 and GLUT3 have a central (M7-12). They are also defined by a signature motif, the “Amotif,” with a role in glucose uptake as canonical members of the Sugar Porter consensus sequence of Gx3[D/E][R/K]xGx[R/K][K/R] (Nishimura et al, (SP) family. GLUT1 and GLUT3 share a fully conserved substrate- 1993). Due to the pseudo-symmetry, the A motif is found twice, located binding site with identical substrate coordination, but differ in the cytosolic loop connecting M2 and M3 of the N-domain and in significantly in transport affinity in line with their physiological the cytosolic loop connecting M8 and M9 of the C-domain. In GLUT1 the ˚ function. Here, we present a 2.4 A crystal structure of GLUT1 in an AmotiftakestheformG84LFVNRFGRR93 and L325FVVERAGRR334.The inward open conformation and compare it with GLUT3 using both A motif is believed to be a key determinant of transport kinetics (Cain structural and functional data. Our work shows that interactions et al, 2000; Jiang et al, 2013; Nomura et al, 2015; Zhang et al, 2015), and it between a cytosolic “SP motif” and a conserved “A motif” sta- may also modulate transport by direct lipid interactions (Martens et al, bilize the outward conformational state and increases substrate 2018).WithintheMFSsuperfamily,theSPfamilyhaveafamily-defining apparent affinity.
    [Show full text]
  • I LITERATURE-BASED DISCOVERY of KNOWN and POTENTIAL NEW
    LITERATURE-BASED DISCOVERY OF KNOWN AND POTENTIAL NEW MECHANISMS FOR RELATING THE STATUS OF CHOLESTEROL TO THE PROGRESSION OF BREAST CANCER BY YU WANG THESIS Submitted in partial fulfillment of the requirements for the degree of Master of Science in Bioinformatics with a concentration in Library and Information Science in the Graduate College of the University of Illinois at Urbana-Champaign, 2019 Urbana, Illinois Adviser: Professor Vetle I. Torvik Professor Erik Russell Nelson i ABSTRACT Breast cancer has been studied for a long period of time and from a variety of perspectives in order to understand its pathogeny. The pathogeny of breast cancer can be classified into two groups: hereditary and spontaneous. Although cancer in general is considered a genetic disease, spontaneous factors are responsible for most of the pathogeny of breast cancer. In other words, breast cancer is more likely to be caused and deteriorated by the dysfunction of a physical molecule than be caused by germline mutation directly. Interestingly, cholesterol, as one of those molecules, has been discovered to correlate with breast cancer risk. However, the mechanisms of how cholesterol helps breast cancer progression are not thoroughly understood. As a result, this study aims to study known and discover potential new mechanisms regarding to the correlation of cholesterol and breast cancer progression using literature review and literature-based discovery. The known mechanisms are further classified into four groups: cholesterol membrane content, transport of cholesterol, cholesterol metabolites, and other. The potential mechanisms, which are intended to provide potential new treatments, have been identified and checked for feasibility by an expert.
    [Show full text]
  • Association Between Tumor Hypoxia and Malignant Progression in Advanced Cancer of the Uterine Cervix1
    (CANCER RHSl-AKCH 56. 45(»-45l5. Octnbcr I. 1996] Association between Tumor Hypoxia and Malignant Progression in Advanced Cancer of the Uterine Cervix1 Michael Höckel,2Karlheinz Schienger, Billur Aral, Margarete Milze, Uwe Schäffer, and Peter Vaupel Department iif Ohsieirics anil üyneciiltiuy /M. H., K. S.. B. A.. U. S.] unti lile Institutes ¡ifPiilholiifty ¡M.M./ und Ph\\inli>K\ ami Paihuiihysii>li>Ky¡P-V.]. University <ifMainz Metileni Schnei. 55/W Mitin:. Genniin\ ABSTRACT ture is evident ( I ). As a consequence, tissue hypoxia results from either insufficient O-, diffusion (chronic hypoxia) or insufficient Experimental tumors contain a significant fraction of microregions that perfusion (acute hypoxia. transient hypoxia. or ischemie hypoxia). are chronically or transiently hvpoxic. Experimental evidence showing Moreover, in vitro and experimental tumor studies showed that that hypoxia (und suhsequent reoxygenation) muy huve a profound impact hypoxia (and subsequent reoxygenation) may have a dramatic on malignant progression and on responsiveness to therapy is growing. I lie clinical relevance of tumor oxygénationin Immun solid malignancies impact on malignant progression in terms of tumor spread and is under ¡mesticatimi. resistance to therapy (2-13). Despite these striking observations in \\ e huve developed and validuted a clinically applicable method for tumor models, the clinical relevance of tumor oxygénation is still measurement of tumor oxygénation in locully udvunced cancer of the unclear. After Thomlinson and Gray (14) presented evidence for uterine cervix using a computerized polarographic electrode system. Ap hypoxic microregions within human tumors from a detailed his- plying this procedure in patients with cervical cancers S3 cm in diameter, topathological study of lung cancers.
    [Show full text]
  • HER Inhibitor Promotes BRAF/MEK Inhibitor-Induced Redifferentiation in Papillary Thyroid Cancer Harboring BRAFV600E
    www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 12), pp: 19843-19854 Research Paper HER inhibitor promotes BRAF/MEK inhibitor-induced redifferentiation in papillary thyroid cancer harboring BRAFV600E Lingxiao Cheng1,*, Yuchen Jin1,*, Min Liu1, Maomei Ruan2, Libo Chen1 1Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China 2Department of Nuclear Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China *Co-first authors Correspondence to: Libo Chen, email: [email protected] Keywords: papillary thyroid cancer, redifferentiation, iodine, glucose, dabrafenib Received: October 20, 2016 Accepted: January 24, 2017 Published: February 28, 2017 ABSTRACT Redifferentiation therapy with BRAF/MEK inhibitors to facilitate treatment with radioiodine represents a good choice for radioiodine-refractory differentiated thyroid carcinoma, but recent initial clinical outcomes were modest. MAPK rebound caused by BRAF/MEK inhibitors-induced activation of HER2/HER3 is a resistance mechanism, and combination with HER inhibitor to prevent MAPK rebound may sensitize BRAFV600E- mutant thyroid cancer cells to redifferentiation therapy. To evaluate if inhibiting both BRAF/MEK and HER can produce stronger redifferetiation effect, we tested the effects of BRAF/MEK inhibitor dabrafenib/selumetinib alone or in combination with HER inhibitor lapatinib on the expression and function of iodine- and glucose-handling genes in BRAFV600E-positive BCPAP and K1 cells, using BHP 2-7 cells harboring RET/ PTC1 rearrangement as control. Herein, we showed that lapatinib prevented MAPK rebound and sensitized BRAFV600E-positive papillary thyroid cancer cells to BRAF/ MEK inhibitors. Dabrafenib/selumetinib alone increased iodine-uptake and toxicity and suppressed glucose-metablism in BRAFV600E-positive papillary thyroid cancer cells.
    [Show full text]
  • Glucose Transporter 3 Is Essential for the Survival of Breast Cancer Cells in the Brain
    cells Article Glucose Transporter 3 Is Essential for the Survival of Breast Cancer Cells in the Brain Min-Hsun Kuo 1,2, Wen-Wei Chang 3 , Bi-Wen Yeh 4,5, Yeh-Shiu Chu 6 , Yueh-Chun Lee 7 and Hsueh-Te Lee 1,2,6,8,* 1 Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei 11529, Taiwan; [email protected] 2 Institute of Anatomy & Cell Biology, National Yang-Ming University, Taipei 11202, Taiwan 3 School of Biomedical Sciences, Chung Shan Medical University, Taichung 40201, Taiwan; [email protected] 4 Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; [email protected] 5 Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan 6 Brain Research Center, National Yang-Ming University, Taipei 11202, Taiwan; [email protected] 7 Department of Radiation Oncology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan; [email protected] 8 Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Yang-Ming University and Academia Sinica, Taipei 11529, Taiwan * Correspondence: [email protected]; Tel.: +886-2-28267073; Fax: +886-2-2821-2884 Received: 15 October 2019; Accepted: 2 December 2019; Published: 4 December 2019 Abstract: Breast cancer brain metastasis commonly occurs in one-fourth of breast cancer patients and is associated with poor prognosis. Abnormal glucose metabolism is found to promote cancer metastasis. Moreover, the tumor microenvironment is crucial and plays an active role in the metabolic adaptations and survival of cancer cells. Glucose transporters are overexpressed in cancer cells to increase glucose uptake.
    [Show full text]
  • Distribution of Glucose Transporters in Renal Diseases Leszek Szablewski
    Szablewski Journal of Biomedical Science (2017) 24:64 DOI 10.1186/s12929-017-0371-7 REVIEW Open Access Distribution of glucose transporters in renal diseases Leszek Szablewski Abstract Kidneys play an important role in glucose homeostasis. Renal gluconeogenesis prevents hypoglycemia by releasing glucose into the blood stream. Glucose homeostasis is also due, in part, to reabsorption and excretion of hexose in the kidney. Lipid bilayer of plasma membrane is impermeable for glucose, which is hydrophilic and soluble in water. Therefore, transport of glucose across the plasma membrane depends on carrier proteins expressed in the plasma membrane. In humans, there are three families of glucose transporters: GLUT proteins, sodium-dependent glucose transporters (SGLTs) and SWEET. In kidney, only GLUTs and SGLTs protein are expressed. Mutations within genes that code these proteins lead to different renal disorders and diseases. However, diseases, not only renal, such as diabetes, may damage expression and function of renal glucose transporters. Keywords: Kidney, GLUT proteins, SGLT proteins, Diabetes, Familial renal glucosuria, Fanconi-Bickel syndrome, Renal cancers Background Because glucose is hydrophilic and soluble in water, lipid Maintenance of glucose homeostasis prevents pathological bilayer of plasma membrane is impermeable for it. There- consequences due to prolonged hyperglycemia or fore, transport of glucose into cells depends on carrier pro- hypoglycemia. Hyperglycemia leads to a high risk of vascu- teins that are present in the plasma membrane. In humans, lar complications, nephropathy, neuropathy and retinop- there are three families of glucose transporters: GLUT pro- athy. Hypoglycemia may damage the central nervous teins, encoded by SLC2 genes; sodium-dependent glucose system and lead to a higher risk of death.
    [Show full text]
  • IGF-I Increases the Recruitment of GLUT4 and GLUT3 Glucose
    European Journal of Endocrinology (2008) 158 361–366 ISSN 0804-4643 CLINICAL STUDY IGF-I increases the recruitment of GLUT4 and GLUT3 glucose transporters on cell surface in hyperthyroidism George Dimitriadis1, Eirini Maratou2, Eleni Boutati1, Anastasios Kollias1, Katerina Tsegka1, Maria Alevizaki3, Melpomeni Peppa1, Sotirios A Raptis1,2 and Dimitrios J Hadjidakis1 1Second Department of Internal Medicine, Research Institute and Diabetes Center,University General Hospital ‘Attikon’, Athens University, 1 Rimini Street, 12462 Haidari, Greece, 2Hellenic National Center for Research, Prevention and Treatment of Diabetes Mellitus and its Complications, 10675 Athens, Greece and 3Department of Clinical Therapeutics, 11528 Athens University, Athens, Greece (Correspondence should be addressed to G Dimitriadis; Email: [email protected], [email protected]) Abstract Objective: In hyperthyroidism, tissue glucose disposal is increased to adapt to high energy demand. Our aim was to examine the regulation of glucose transporter (GLUT) isoforms by IGF-I in monocytes from patients with hyperthyroidism. Design and methods: Blood (20 ml) was drawn from 21 healthy and 10 hyperthyroid subjects. The abundance of GLUT isoforms on the monocyte plasma membrane was determined in the absence and presence of IGF-I (0.07, 0.14, and 0.7 nM) using flow cytometry. Anti-CD14-phycoerythrin monocional antibody was used for monocyte gating. GLUT isoforms were determined after staining the cells with specific antisera to GLUT3 and GLUT4. Results: In monocytes from the euthyroid subjects, IGF-I increased the abundance of GLUT3 and GLUT4 on the monocyte surface by 25 and 21% respectively (P!0.0005 with repeated measures ANOVA). Hyperthyroidism increased the basal monocyte surface GLUT3 and GLUT4; in these cells, IGF-I had a marginal but highly significant effect (PZ0.003, with repeated measures ANOVA) on GLUT3 (11%) and GLUT4 (10%) translocation on the plasma membrane.
    [Show full text]
  • A High-Throughput Screen Identifies That CDK7 Activates Glucose
    ARTICLE https://doi.org/10.1038/s41467-019-13334-8 OPEN A high-throughput screen identifies that CDK7 activates glucose consumption in lung cancer cells Chiara Ghezzi1,2, Alicia Wong1,2, Bao Ying Chen1,2, Bernard Ribalet3, Robert Damoiseaux1,2,4 & Peter M. Clark 1,2,4,5* Elevated glucose consumption is fundamental to cancer, but selectively targeting this path- way is challenging. We develop a high-throughput assay for measuring glucose consumption 1234567890():,; and use it to screen non-small-cell lung cancer cell lines against bioactive small molecules. We identify Milciclib that blocks glucose consumption in H460 and H1975, but not in HCC827 or A549 cells, by decreasing SLC2A1 (GLUT1) mRNA and protein levels and by inhibiting glucose transport. Milciclib blocks glucose consumption by targeting cyclin- dependent kinase 7 (CDK7) similar to other CDK7 inhibitors including THZ1 and LDC4297. Enhanced PIK3CA signaling leads to CDK7 phosphorylation, which promotes RNA Poly- merase II phosphorylation and transcription. Milciclib, THZ1, and LDC4297 lead to a reduction in RNA Polymerase II phosphorylation on the SLC2A1 promoter. These data indi- cate that our high-throughput assay can identify compounds that regulate glucose con- sumption and that CDK7 is a key regulator of glucose consumption in cells with an activated PI3K pathway. 1 Crump Institute for Molecular Imaging, University of California, Los Angeles, CA 90095, USA. 2 Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA. 3 Department of Physiology, University of California, Los Angeles, CA 90095, USA. 4 California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA.
    [Show full text]
  • The Oxygen Effect in the Development of Radiosensitizers
    Translational Oncology Volume 4 Number 4 August 2011 pp. 189–198 189 www.transonc.com Six Degrees of Separation: Bryan T. Oronsky*, Susan J. Knox† and Jan Scicinski* The Oxygen Effect *RadioRx, Inc, Mountain View, CA, USA; †Department in the Development of Radiation Oncology, Stanford University Medical of Radiosensitizers Center, Stanford, CA, USA Abstract The popular theory six degrees of separation is used in this review as an analogy to relate all radiosensitization to oxygen. As the prime mover of all radiosensitizers, the pervasive influence of oxygen has consciously or uncon- sciously influenced the direction of research and development and provided the benchmark against which all other compounds and approaches are measured. It is the aim of this review to develop the six degrees of separation from oxygen analogy as a unifying framework for conceptually organizing the field and for giving context to its varied subspecializations and theories. Under such a framework, it would become possible for one area to consider ques- tions and problems found in other areas of radiosensitization, using a common analogy, that would allow for further development and unification of this multifaceted discipline. In this review, approaches to the development of radio- sensitizers and the current state of research in this field are discussed, including promising new agents in various stages of clinical development. Translational Oncology (2011) 4, 189–198 Introduction support metabolic pathways. The ability of more aggressive cancer The view that everything is connected to everything else according to cells to survive hypoxic conditions leads to selection against apoptosis the popular six degrees of separation theory finds corroboration on a and an increased resistance to chemotherapy, as well as a propensity therapeutic level in the field of radiosensitization.
    [Show full text]
  • Causes and Consequences of Increased Glucose Metabolism of Cancers
    Causes and Consequences of Increased Glucose Metabolism of Cancers Robert J. Gillies, Ian Robey, and Robert A. Gatenby University of Arizona, Tucson, Arizona does not appear to be a significant adaptive advantage of using In this review we examine the mechanisms (causes) underlying glycolysis when oxygen is present (the Warburg effect). Yet, the increased glucose consumption observed in tumors within its prevalence in the overwhelming majority of metastatic a teleological context (consequences). In other words, we will tumors is compelling evidence that aerobic glycolysis plays a ask not only ‘‘How do cancers have high glycolysis?’’ but also, very significant role in promoting tumor development. ‘‘Why?’’ We believe that the insights gained from answering the latter question support the conclusion that elevated glucose To address this, the evolutionary dynamics of carcinogen- consumption is a necessary component of carcinogenesis. esis have been modeled using several mathematic methods, Specifically we propose that glycolysis is elevated because it including information theory, evolutionary game theory, produces acid, which provides an evolutionary advantage to reaction–diffusion models, and modified cellular automata cancer cells vis-a-vis` normal parenchyma into which they invade. (2–12). Insights from these models combined with modern Key Words: cancer; glucose; metabolism; carcinogenesis; imaging, what we have termed ‘‘imag(in)ing,’’ have demon- acid-base; somatic evolution strated that hypoxia and acidosis develop inevitably in the J Nucl Med 2008; 49:24S–42S microenvironment of premalignant epithelial tumors, such as DOI: 10.2967/jnumed.107.047258 ductal carcinoma in situ (DCIS). This results from aberrant proliferation that carries cells away from their underlying blood supply, which remains on the opposite side of an in- tact basement membrane (BM).
    [Show full text]
  • Pyruvate Dehydrogenase Kinase As a Potential Therapeutic Target for Malignant Gliomas
    REVIEW ARTICLE Brain Tumor Res Treat 2013;1:57-63 / Print ISSN 2288-2405 / Online ISSN 2288-2413 online © ML Comm Pyruvate Dehydrogenase Kinase as a Potential Therapeutic Target for Malignant Gliomas Mithilesh Kumar Jha, Kyoungho Suk Department of Pharmacology, Brain Science & Engineering Institute, Kyungpook National University School of Medicine, Daegu, Korea Metabolic aberrations in the form of altered flux through key metabolic pathways are the major hall- marks of several life-threatening malignancies including malignant gliomas. These adaptations play an important role in the enhancement of the survival and proliferation of gliomas at the expense of the Received August 12, 2013 surrounding normal/healthy tissues. Recent studies in the field of neurooncology have directly targeted Revised August 14, 2013 the altered metabolic pathways of malignant tumor cells for the development of anti-cancer drugs. Accepted September 23, 2013 Aerobic glycolysis due to elevated production of lactate from pyruvate regardless of oxygen availability Correspondence is a common metabolic alteration in most malignancies. Aerobic glycolysis offers survival advantages Kyoungho Suk in addition to generating substrates such as fatty acids, amino acids and nucleotides required for the Department of Pharmacology, rapid proliferation of cells. This review outlines the role of pyruvate dehydrogenase kinase (PDK) in glio- Kyungpook National University mas as an inhibitor of pyruvate dehydrogenase that catalyzes the oxidative decarboxylation of pyru- School of Medicine, vate. An in-depth investigation on the key metabolic enzyme PDK may provide a novel therapeutic ap- 680 Gukchaebosang-ro, Jung-gu, Daegu 700-842, Korea proach for the treatment of malignant gliomas. Tel: +82-53-420-4835 Fax: +82-53-256-1566 Key Words Pyruvate dehydrogenase kinase; Glioma; Gliomagenesis; Dichloroacetate; E-mail: [email protected] Hypoxia-inducible factor.
    [Show full text]