DOCSLIB.ORG

The Cell Membrane and Cell Signals As Targets in Cancer Chemotherapy AACR,EORTC, and Bacrspecialconferencein Cancer Research1

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Cell Membrane and Cell Signals As Targets in Cancer Chemotherapy AACR,EORTC, and Bacrspecialconferencein Cancer Research1 [CANCER RESEARCH 50, 2203-22! I. April 1. 1990] Meeting Report The Cell Membrane and Cell Signals as Targets in Cancer Chemotherapy AACR,EORTC, and BACRSpecialConferencein Cancer Research1 The potential of the cell membrane and intracellular signal were outlined by Michael Berridge. In describing this increas ling pathways as targets for anticancer drug development was ingly complex network of events initiated at the cell surface, he the subject of a meeting held in the tranquil surroundings of drew attention to the potential role of oncogene products, such Queens' College, Cambridge University, UK, on September as sis, src, erb-B, andfms, and speculated upon these and other 14-16, 1989. It was the first meeting held outside the United key elements of the cascades as potential targets for drugs. In States or Canada organized by the American Association for particular, Dr. Berridge hypothesized a role for so-called "in tegrators'" in the cascades: these integrator proteins lie at the Cancer Research and was sponsored in association with The European Organization for Research and Treatment of Cancer crossroads of what is envisioned as a series of branching sig (Pharmacokinetics and Metabolism Group) and the British nalling networks and he suggested that they may be attractive Association for Cancer Research. Delegates at the conference as potential targets for pharmacological intervention. Two such came from four continents: Europe, North America, Australia, integrator targets were phospholipase C and protein kinase C, and Asia. The meeting was held in brand new conference the latter proving to be a focal point for many of the subsequent facilities on the campus of a very old college, founded in the presentations. 15th century by the Queens of Henry VI and Edward IV. The complexity and the elegant integration of signal cascades The origin of the meeting was widespread frustration with were illustrated with a detailed account of recent advances in the slow pace of development of effective new anticancer treat the understanding of the role of the inositol phospholipids in ments and the belief that new targets other than the traditional calcium signalling. The now well characterized bifurcating cas ones of the cell nucleus and DNA might be one way to overcome cade of receptor-mediated G-protein2-linked hydrolysis of phos- this stasis. The aim of the organizers was to bring together the phatidylinositol-4,5-bisphosphate to yield diacylglycerol and foremost scientists working on basic aspects of cell membrane IP}( 1,4,5) was described. Berridge outlined a hypothesis to function and mechanisms of intracellular signalling related to explain the nature of the calcium oscillations induced by the the control of cell proliferation, transformation, differentiation, release of IP3(1,4,5). He discussed ideas concerning the second and metastasis and chemists, cancer pharmacologists, experi stage of calcium signalling, after IP,(l,4,5)-mediated calcium mental chemotherapists, and cancer clinicians in whose hands release from the endoplasmic reticulum where the influx of the ultimate development of new drugs will lie. The interest calcium from the extracellular milieu occurs via non-voltage- was to achieve a cross-fertilization of ideas and to stimulate dependent calcium channels. Of particular interest to the 240 further development in this exciting area. Each session began assembled scientists was the account of the emergence of, and with an overview of the basic science foundations, followed by possible roles for, the recently discovered phosphatidylinositol- presentations specifically devoted to anticancer drug develop 3-phosphate. Work on the function of the proto-oncogene c-src ment. suggests that this novel inositol lipid may be formed via an association between middle T antigen/c-src and a unique, type 1, phosphatidylinositol-3'-kinase. Whitman et al. (1) have sug Membrane and Signalling Targets for Drug Development (Chair gested that the 3-isomer may be a regulator of the inositol lipid person: John A. Hickman) cascade, in a manner analogous to that of fructose 2,6-bisphos- phate in glycolysis, and Berridge speculated that it may amplify The two opening presentations of the meeting, by Michael a normal hormonal response by mobilizing discrete hormone- Berridge (Cambridge University, UK) and by Timothy Rink insensitive pools of phosphatidylinositol. Some of these pools (Smith Kline and French Research, Welwyn, UK), set the scene may be associated with the control of the structure and function by reviewing the nature of signal cascades initiated at the cell of the cytoskeleton. Such a system would constitute an impor membrane and by tackling the fundamental problem of the tant feature in a cell which contains elevated tyrosine kinase opportunity for selective drug action at this locus. activity associated with a number of oncogenes, also potential The bare bones of what is known about the cascades which targets for selective drug action (see below), and may explain start after growth factors and other ligands bind to receptors the "permissive" effects of insulin on the mitogenic signals Received 12/7/89. provided by non-tyrosine kinase-Iinked mitogens, such as bom- 1This meeting was sponsored jointly by the American Association for Cancer besin and vasopressin systems, described by Rozengurt in a Research (AACR). the British Association for Cancer Research (BACR), and the European Organization for Research and Treatment of Cancer (EORTC) (Phar later session at the meeting (see below). macokinetics and Metabolism Group) and took place at Queens's College, Uni The inhibition of inositol lipid metabolism by drugs was versity of Cambridge, UK, September 14-16, 1989. The organizing committee discussed later in the proceedings by Peter Downes, but Ber was: for the AACR—Garth Powis, Mayo Clinic & Foundation (Rochester, MN); Thomas R. Tritton, University of Vermont (Burlington. VT); Edward J. Modest. ridge chose to point out, as a possible precedent for further Boston University (Boston, MA); and Garth L. Nicolson, M.D. Anderson Cancer selective drug intervention, the perhaps surprising selectivity of Center (Houston, TX); for BACR—John A. Hickman, Aston University (Bir mingham. UK); Timothy J. Rink, Smith Kline and French Research Ltd. (Wel 2The abbreviations used are: G proteins, guanine nucleotide-binding proteins; wyn, Hertfordshire, UK); and Anne R. Simmonds, Kirby-Warrick Pharmaceuti IP3(1,4,5), inositol (l,4.5)-trisphosphate; [Ca1*],. intracellular free Ca2* concen cals (Bury St. Edmonds, Suffolk, UK); and for EORTC—Paul Workman, Medical tration; PAF, platelet-activating factor; EGF, epidermal growth factor; ABMT. Research Council Clinical Oncology and Radiotherapeutics Unit (Cambridge, autologous bone marrow transplantation; ET-18-OCHj, l-O-octadecyl-2-O- UK); Jean-Pierre Abita, St. Louis Hospital. (Paris, France); and Wolfgang E. methyl-roc-glycero-3-phosphocholine; HPC, hexadecylphosphocholine; PKC, Berdel, Technical University of Munich (Munich, FRG). protein kinase C; TGF-/3, transforming growth factor ft; [3H]PDBu. ('Hjphorbol- Reprint requests should be addressed to: Dr. Garth Powis, Department of 12-13-dibutyrate; RA, retinoic acid; CR, complete remission; GM-CSF, granu- Pharmacology, Mayo Clinic and Foundation, 200 First Street, S.W., Rochester, locyte/macrophage colony-stimulating factor; G-CSF, granulocyte colony-stim MN 55905. ulating factor; M-CSF. macrophage colony-stimulating factor. 2203 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1990 American Association for Cancer Research. MEETING REPORT lithium as an inhibitor of inositol lipid metabolism. Lithium Ben de Kruijff (University of Utrecht, The Netherlands) noncompetitively inhibits the hydrolysis of key inositol phos continued the theme of doxorubicin-membrane interactions by phates prior to the reincorporation of inositol into phospho- describing his group's use of NMR spectroscopy to study the lipid, thereby depleting the cell of inositol. The selectivity of problem. Since doxorubicin is positively charged under phys this action arises from the higher turnover of the inositol lipids iological conditions, it has special affinity for acidic phospho- in overactive cells. The concept of this type of inhibition, lipids, particularly cardiolipin, as described above. This lipid selective suppression of overactive pathways, might give pur promotes the formation of nonbilayer structures (such as hex chase for novel drugs. agonal or inverted phases) in membranes, which can be clearly- Serendipity will no doubt continue to play a major role in distinguished by NMR techniques. Doxorubicin stabilizes car drug discovery, and Tim Rink was careful to point out that the diolipin from forming nonbilayer structures and, as a result, many classes of therapeutically useful membrane-active agents, inhibits all mitochondrial enzymes which are known to specif including the cardiac glycoside ouabain, would not have sur ically interact with cardiolipin. This inhibition in turn is hy vived the logical scrutiny of a rational team of drug designers. pothesized to be involved in the notorious cumulative dose- Undoubtedly, the best example is that of the calcium antago dependent cardiomyopathy caused by doxorubicin, and whole nists: the ubiquity of voltage-dependent calcium channels would animal "P NMR studies in fact revealed a significant drop in have suggested no avenue for selective action but, once again, energy-rich phosphates upon doxorubicin administration.
Load more

Recommended publications
  • Chemistry and Physics of Lipids Effects of Ether Vs. Ester Linkage On
    Chemistry and Physics of Lipids 160 (2009) 33–44 Contents lists available at ScienceDirect Chemistry and Physics of Lipids journal homepage: www.elsevier.com/locate/chemphyslip Effects of ether vs. ester linkage on lipid bilayer structure and water permeability S. Deren Guler a, D. Dipon Ghosh b, Jianjun Pan a, John C. Mathai c, Mark L. Zeidel c, John F. Nagle a,b, Stephanie Tristram-Nagle a,∗ a Department of Physics, Carnegie Mellon University, Pittsburgh, PA 15213, USA b Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213, USA c Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Cambridge, MA 02139, USA article info abstract Article history: The structure and water permeability of bilayers composed of the ether-linked lipid, dihexadecylphos- Received 29 January 2009 phatidylcholine (DHPC), were studied and compared with the ester-linked lipid, dipalmitoylphosphadit- Received in revised form 29 March 2009 dylcholine (DPPC). Wide angle X-ray scattering on oriented bilayers in the fluid phase indicate that the Accepted 26 April 2009 area per lipid A is slightly larger for DHPC than for DPPC. Low angle X-ray scattering yields A = 65.1 Å2 for Available online 3 May 2009 ◦ −13 DHPC at 48 C. LAXS data provide the bending modulus, KC = 4.2 × 10 erg, and the Hamaker parame- ter H =7.2× 10−14 erg for the van der Waals attractive interaction between neighboring bilayers. For the Keywords: low temperature phases with ordered hydrocarbon chains, we confirm the transition from a tilted L␤ Ether lipid ◦ gel phase to an untilted, interdigitated L␤I phase as the sample hydrates at 20 C.
    [Show full text]
  • Discovery of Inhibitors for the Ether Lipid-Generating Enzyme AGPS As Anti-Cancer Agents † # ‡ # § # † § Valentina Piano, , Daniel I
    Articles pubs.acs.org/acschemicalbiology Discovery of Inhibitors for the Ether Lipid-Generating Enzyme AGPS as Anti-Cancer Agents † # ‡ # § # † § Valentina Piano, , Daniel I. Benjamin, , Sergio Valente, , Simone Nenci, Biagina Marrocco, § ∥ ⊥ ‡ † Antonello Mai, , Alessandro Aliverti, Daniel K. Nomura,*, and Andrea Mattevi*, † Department of Biology and Biotechnology, University of Pavia, via Ferrata 9, 27100 Pavia, Italy ‡ Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California 94720, United States § Department of Drug Chemistry and Technologies, University “La Sapienza”, P. le A. Moro 5, Roma 00185, Italy ∥ Pasteur Institute, Cenci Bolognetti Foundation, P.le A. Moro 5, Roma 00185, Italy ⊥ Department of Biosciences, University of Milano, Via Festa del Perdono, 7, 20122 Milano, Italy *S Supporting Information ABSTRACT: Dysregulated ether lipid metabolism is an important hallmark of cancer cells. Previous studies have reported that lowering ether lipid levels by genetic ablation of the ether lipid-generating enzyme alkyl-glycerone phosphate synthase (AGPS) lowers key structural and oncogenic ether lipid levels and alters fatty acid, glycerophospholipid, and eicosanoid metabolism to impair cancer pathogenicity, indicating that AGPS may be a potential therapeutic target for cancer. In this study, we have performed a small-molecule screen to identify candidate AGPS inhibitors. We have identified several lead AGPS inhibitors and have structurally characterized their interactions with the enzyme and show that these inhibitors bind to distinct portions of the active site. We further show that the lead AGPS inhibitor 1a selectively lowers ether lipid levels in several types of human cancer cells and impairs their cellular survival and migration. We provide here the first report of in situ-active pharmacological tools for inhibiting AGPS, which may provide chemical scaffolds for future AGPS inhibitor development for cancer therapy.
    [Show full text]
  • Hot Topics in Neural Membrane Lipidology
    A.A. Farooqui Hot Topics in Neural Membrane Lipidology ▶ Focuses exclusively on lipid mediators and neurological disorders Not only do glycerophospholipid, sphingolipid, and cholesterol-derived lipid mediators facilitate the transfer of messages from one cell to another, they also facilitate communication among subcellular organelles. Hot Topics in Neural Membrane Lipidology provides readers with a cutting-edge, comprehensive review of these lipid mediators, their roles and association with neurological disorders, and the future direction of research on the topic. This monograph provides readers with critical data and is particularly accessible to neuroscience graduate students, teachers, and researchers. It can be used as a supplemental text for a range of neuroscience courses. Clinicians and pharmacologists will find this book useful for understanding molecular aspects of lipid mediators in acute neural trauma like stroke, spinal cord trauma, head injury, and neurodegenerative diseases such as Alzheimer disease, Parkinson disease, and Huntington disease. 2009, XXIV, 408 p. 62 illus. About the Author: Printed book Akhlaq A. Farooqui is a leader in the field of brain phospholipases A2, bioactive ether lipid metabolism, and glutamate-mediated neurotoxicity. He has discovered the stimulation of Hardcover plasmalogen-selective phospholipase A2 activity in brains from patients with Alzheimer ▶ 199,99 € | £179.99 | $249.99 disease, and published cutting edge research on the generation and identification of ▶ *213,99 € (D) | 219,99 € (A) | CHF 236.00 glycerophospholipid, sphingolipid, and cholesterol-derived lipid mediators in kainic acid neurotoxicity. Dr. Farooqui has authored three monographs: Glycerophospholipids eBook in Brain: Phospholipase A2 in Neurological Disorders (2007); Neurochemical Aspects of Excitotoxicity (2008); and Metabolism and Functions of Bioactive Ether Lipids in Brain Available from your bookstore or (2008).
    [Show full text]
  • The Ether Lipid-Deficient Mouse: Tracking Down Plasmalogen Functions ⁎ Karin Gorgas A, Andre Teigler B, Dorde Komljenovic A, Wilhelm W
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1763 (2006) 1511–1526 www.elsevier.com/locate/bbamcr Review The ether lipid-deficient mouse: Tracking down plasmalogen functions ⁎ Karin Gorgas a, Andre Teigler b, Dorde Komljenovic a, Wilhelm W. Just b, a Institut für Anatomie und Zellbiologie, Abteilung Medizinische Zellbiologie, Im Neuenheimer Feld 307, D-69120 Heidelberg, Germany b Biochemie-Zentrum der Universität Heidelberg (BZH), Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany Received 29 June 2006; received in revised form 15 August 2006; accepted 23 August 2006 Available online 30 August 2006 Abstract Chemical and physico-chemical properties as well as physiological functions of major mammalian ether-linked glycerolipids, including plasmalogens were reviewed. Their chemical structures were described and their effect on membrane fluidity and membrane fusion discussed. The recent generation of mouse models with ether lipid deficiency offered the possibility to study ether lipid and particularly plasmalogen functions in vivo. Ether lipid-deficient mice revealed severe phenotypic alterations, including arrest of spermatogenesis, development of cataract and defects in central nervous system myelination. In several cell culture systems lack of plasmalogens impaired intracellular cholesterol distribution affecting plasma membrane functions and structural changes of ER and Golgi cisternae. Based on these phenotypic anomalies that were accurately described conclusions were drawn on putative functions of plasmalogens. These functions were related to cell–cell or cell–extracellular matrix interactions, formation of lipid raft microdomains and intracellular cholesterol homeostasis. There are several human disorders, such as Zellweger syndrome, rhizomelic chondrodysplasia punctata, Alzheimer’s disease, Down syndrome, and Niemann–Pick type C disease that are distinguished by altered tissue plasmalogen concentrations.
    [Show full text]
  • Bioactive Ether Lipids: Primordial Modulators of Cellular Signaling
    H OH metabolites OH Review Bioactive Ether Lipids: Primordial Modulators of Cellular Signaling Nikhil Rangholia 1,† , Tina M. Leisner 2 and Stephen P. Holly 1,* 1 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Campbell University, Buies Creek, NC 27506, USA; [email protected] 2 Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; [email protected] * Correspondence: [email protected] † Current address: Frontage Laboratories Inc., 75 E. Uwchian Ave, STE 100, Exton, PA 19341, USA. Abstract: The primacy of lipids as essential components of cellular membranes is conserved across taxonomic domains. In addition to this crucial role as a semi-permeable barrier, lipids are also increasingly recognized as important signaling molecules with diverse functional mechanisms ranging from cell surface receptor binding to the intracellular regulation of enzymatic cascades. In this review, we focus on ether lipids, an ancient family of lipids having ether-linked structures that chemically differ from their more prevalent acyl relatives. In particular, we examine ether lipid biosynthesis in the peroxisome of mammalian cells, the roles of selected glycerolipids and glycerophospholipids in signal transduction in both prokaryotes and eukaryotes, and finally, the potential therapeutic contributions of synthetic ether lipids to the treatment of cancer. Keywords: ether lipid; alkylglycerol; signaling; signal transduction; glycerolipid; glycerophospho- lipid; apoptosis; platelet; cancer 1. Introduction Citation: Rangholia, N.; Leisner, Much like many other types of organic molecules, lipids are essential for life—even T.M.; Holly, S.P.
    [Show full text]
  • Antiproliferative Effect of Two Novel Palmitoylcarnitine Analogs
    Eur. J. Biochem. 266, 855±864 (1999) q FEBS 1999 Anti-proliferative effect of two novel palmitoyl-carnitine analogs, selective inhibitors of protein kinase C conventional isoenzymes Tea Garcia-Huidobro, Enrique Valenzuela, Andrea V. Leisewitz, Jaime Valderrama and Miguel Bronfman Departamento de BiologõÂa Celular y Molecular, Facultad de Ciencias BioloÂgicas y Facultad de QuõÂmica, P. Universidad CatoÂlica de Chile, Santiago, Chile Previous studies have shown that palmitoyl-carnitine is an anti-proliferative agent and a protein kinase C inhibitor. Two new palmitoyl-carnitine analogs were synthesized by replacing the ester bond with a metabolically more stable ether bond. An LD50 value in the nm range was found in anti-proliferative assays using HL-60 cells and was dependent on the alkyl-chain length. The inhibitory action of these water-soluble compounds on protein kinase C in vitro was greatly increased with respect to palmitoyl-carnitine and was dependent on the length of the alkyl chain. Its effect was mediated by an increase in the enzyme's requirement for phosphatidylserine. Inhibition of the in situ phosphorylation of a physiological platelet protein kinase C substrate and of phorbol ester-induced differentiation of HL-60 cells was also observed. Finally, to test for isoenzyme selectivity, several human recombinant protein kinase C isoforms were used. Only the Ca2+-dependent classic protein kinase Cs (a, bI, bII and g) were inhibited by these compounds, yet the activities of casein kinase I, Ca2+/calmodulin-dependent kinase and cAMP-dependent protein kinase were unaffected. Thus, these novel inhibitors appear to be both protein kinase C and isozyme selective.
    [Show full text]
  • The TMEM189 Gene Encodes Plasmanylethanolamine Desaturase Which Introduces the Characteristic Vinyl Ether Double Bond Into Plasmalogens
    The TMEM189 gene encodes plasmanylethanolamine desaturase which introduces the characteristic vinyl ether double bond into plasmalogens Ernst R. Wernera,1, Markus A. Kellerb, Sabrina Sailera, Katharina Lacknera, Jakob Kochb, Martin Hermannc, Stefan Coassind, Georg Golderera, Gabriele Werner-Felmayera, Raphael A. Zoellere, Nicolas Hulof, Johannes Bergerg, and Katrin Watschingera,1 aInstitute of Biological Chemistry, Biocenter, Medical University of Innsbruck, A-6020 Innsbruck, Austria; bInstitute of Human Genetics, Medical University of Innsbruck, A-6020 Innsbruck, Austria; cUniversity Clinic for Anesthesiology and General Intensive Care Medicine, Medical University of Innsbruck, A-6020 Innsbruck, Austria; dInstitute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, A-6020 Innsbruck, Austria; eDepartment of Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118; fInstitute of Genetics and Genomics, University of Geneva, 1211 Geneva 4, Switzerland; and gDepartment of Pathobiology of the Nervous System, Medical University of Vienna, 1090 Vienna, Austria Edited by Benjamin F. Cravatt, Scripps Research Institute, La Jolla, CA, and approved February 26, 2020 (received for review October 7, 2019) A significant fraction of the glycerophospholipids in the human body severe clinical outcomes, including impaired neural development, is composed of plasmalogens, particularly in the brain, cardiac, and bone deformation, and premature death. The initial peroxisomal immune cell membranes. A decline in these lipids has been observed steps of human plasmalogen biosynthesis have been well charac- in such diseases as Alzheimer’s and chronic obstructive pulmonary terized to require the genes GNPAT (11, 12), AGPS (13), and disease. Plasmalogens contain a characteristic 1-O-alk-1′-enyl ether DHRS7B (14). Further downstream steps occurring in the en- (vinyl ether) double bond that confers special biophysical, biochemi- doplasmic reticulum are less well understood, however.
    [Show full text]
  • The TMEM189 Gene Encodes Plasmanylethanolamine Desaturase Which Introduces the Characteristic Vinyl Ether Double Bond Into Plasmalogens
    The TMEM189 gene encodes plasmanylethanolamine desaturase which introduces the characteristic vinyl ether double bond into plasmalogens Ernst R. Wernera,1, Markus A. Kellerb, Sabrina Sailera, Katharina Lacknera, Jakob Kochb, Martin Hermannc, Stefan Coassind, Georg Golderera, Gabriele Werner-Felmayera, Raphael A. Zoellere, Nicolas Hulof, Johannes Bergerg, and Katrin Watschingera,1 aInstitute of Biological Chemistry, Biocenter, Medical University of Innsbruck, A-6020 Innsbruck, Austria; bInstitute of Human Genetics, Medical University of Innsbruck, A-6020 Innsbruck, Austria; cUniversity Clinic for Anesthesiology and General Intensive Care Medicine, Medical University of Innsbruck, A-6020 Innsbruck, Austria; dInstitute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, A-6020 Innsbruck, Austria; eDepartment of Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118; fInstitute of Genetics and Genomics, University of Geneva, 1211 Geneva 4, Switzerland; and gDepartment of Pathobiology of the Nervous System, Medical University of Vienna, 1090 Vienna, Austria Edited by Benjamin F. Cravatt, Scripps Research Institute, La Jolla, CA, and approved February 26, 2020 (received for review October 7, 2019) A significant fraction of the glycerophospholipids in the human body severe clinical outcomes, including impaired neural development, is composed of plasmalogens, particularly in the brain, cardiac, and bone deformation, and premature death. The initial peroxisomal immune cell membranes. A decline in these lipids has been observed steps of human plasmalogen biosynthesis have been well charac- in such diseases as Alzheimer’s and chronic obstructive pulmonary terizedtorequirethegenesGNPAT (11, 12), AGPS (13), and disease. Plasmalogens contain a characteristic 1-O-alk-1′-enyl ether DHRS7B (14). Further downstream steps occurring in the en- (vinyl ether) double bond that confers special biophysical, biochemi- doplasmic reticulum are less well understood, however.
    [Show full text]
  • Live-Cell Lipid Biochemistry Reveals a Role of Diacylglycerol Side-Chain Composition for Cellular Lipid Dynamics and Protein Affinities
    Live-cell lipid biochemistry reveals a role of diacylglycerol side-chain composition for cellular lipid dynamics and protein affinities Milena Schuhmachera, Andreas T. Grasskampb, Pavel Barahtjana, Nicolai Wagnera, Benoit Lombardota, Jan S. Schuhmachera, Pia Salac,d, Annett Lohmanna, Ian Henrya, Andrej Shevchenkoa, Ünal Coskunc,d, Alexander M. Walterb,1, and André Nadlera,1 aMax Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany; bLeibniz-Forschungsinstitut für Molekulare Pharmakologie, 13125 Berlin, Germany; cPaul Langerhans Institute Dresden, Helmholtz Zentrum München, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; and dGerman Center for Diabetes Research, 85764 Neuherberg, Germany Edited by Satyajit Mayor, National Centre for Biological Sciences, Bangalore, India, and approved February 24, 2020 (received for review July 24, 2019) Every cell produces thousands of distinct lipid species, but insight (16) or the reciprocal regulation of ceramide species during Toll- into how lipid chemical diversity contributes to biological signaling like receptor signaling in innate immunity (17). DAGs appear to is lacking, particularly because of a scarcity of methods for quanti- be prime targets to study the importance of lipid heterogeneity in tatively studying lipid function in living cells. Using the example of cell signaling, as they act as second messengers at the plasma diacylglycerols, prominent second messengers, we here investigate membrane and function in many cellular processes, including in- whether lipid chemical diversity can provide a basis for cellular signal sulin signaling, ion channel regulation, and neurotransmitter release specification. We generated photo-caged lipid probes, which allow (18, 19). Many of these processes involve effector proteins such as acute manipulation of distinct diacylglycerol species in the plasma protein kinase C (PKC) isoforms, which are recruited to cellular membrane.
    [Show full text]
  • Ether Lipid and Sphingolipid Expression Patterns Are G-Protein Coupled
    bioRxiv preprint doi: https://doi.org/10.1101/2020.07.20.212894; this version posted July 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Ether lipid and sphingolipid expression patterns are G-protein coupled 2 estrogen receptor 1-dependently altered in breast cancer cells 3 Lisa Hahnefeld1, Lisa Gruber1, Nina Schömel1, Caroline Fischer1, Peter Mattjus2, Robert 4 Gurke1,3, Martina Beretta4, Nerea Ferreirós1, Gerd Geisslinger1,3, Marthe-Susanna Wegner1,4 5 1pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang 6 Goethe University, Theodor Stern-Kai 7, 60590 Frankfurt am Main, Germany. 7 2Åbo Akademi University, Biochemistry, Faculty of Science and Engineering Artillerigatan 6A, 8 III, BioCity FI-20520 Turku, Finland. 9 3Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Branch for 10 Translational Medicine and Pharmacology TMP, Theodor Stern-Kai 7, 60590 Frankfurt am 11 Main, Germany. 12 4School of Biotechnology and Biomolecular Sciences, University of New South Wales, 13 Sydney, New South Wales 2052, Australia. 14 15 16 17 18 19 20 21 22 Corresponding author: 23 24 Marthe-Susanna Wegner 25 School of Biotechnology & Biomolecular Sciences 26 UNSW SYDNEY NSW 2052 AUTRALIA 27 Phone: +61 (2) 9385 6516 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.20.212894; this version posted July 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
    [Show full text]
  • Structural and Functional Roles of Ether Lipids John M
    Washington University School of Medicine Digital Commons@Becker Open Access Publications 2018 Structural and functional roles of ether lipids John M. Dean Irfan J. Lodhi Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Protein Cell 2018, 9(2):196–206 DOI 10.1007/s13238-017-0423-5 Protein & Cell REVIEW Structural and functional roles of ether lipids John M. Dean, Irfan J. Lodhi& Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA & Correspondence: [email protected] (I. J. Lodhi) Received March 15, 2017 Accepted April 25, 2017 ABSTRACT found in the brain, heart, spleen, and white blood cells, while Cell liver has scant amount of intracellular ether lipids (Braver- Ether lipids, such as plasmalogens, are peroxisome- & man and Moser, 2012). derived glycerophospholipids in which the hydrocarbon Plasmalogens are the most common form of ether lipids chain at the sn-1 position of the glycerol backbone is and are characterized by a cis double bond adjacent to the attached by an ether bond, as opposed to an ester bond ether linkage. Plasmalogens were serendipitously discov- in the more common diacyl phospholipids. This seem- ered in 1924 by Feulgen and Voit while staining tissue sec- ingly simple biochemical change has profound struc- Protein tions with a nuclear stain that reacts with aldehydes released tural and functional implications. Notably, the tendency by acid hydrolysis of DNA (Snyder, 1999). Because the acid of ether lipids to form non-lamellar inverted hexagonal treatment also resulted in breakdown of the vinyl ether bond structures in model membranes suggests that they have of plasmalogens to generate aldehydes, the researchers a role in facilitating membrane fusion processes.
    [Show full text]
  • Mitochondrial Targeting Involving Cholesterol-Rich Lipid Rafts in the Mechanism of Action of the Antitumor Ether Lipid and Alkylphospholipid Analog Edelfosine
    pharmaceutics Review Mitochondrial Targeting Involving Cholesterol-Rich Lipid Rafts in the Mechanism of Action of the Antitumor Ether Lipid and Alkylphospholipid Analog Edelfosine Faustino Mollinedo * and Consuelo Gajate Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), Laboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine, C/Ramiro de Maeztu 9, E-28040 Madrid, Spain; [email protected] * Correspondence: [email protected] Abstract: The ether lipid edelfosine induces apoptosis selectively in tumor cells and is the prototypic molecule of a family of synthetic antitumor compounds collectively known as alkylphospholipid analogs. Cumulative evidence shows that edelfosine interacts with cholesterol-rich lipid rafts, endo- plasmic reticulum (ER) and mitochondria. Edelfosine induces apoptosis in a number of hematological cancer cells by recruiting death receptors and downstream apoptotic signaling into lipid rafts, whereas it promotes apoptosis in solid tumor cells through an ER stress response. Edelfosine-induced apop- tosis, mediated by lipid rafts and/or ER, requires the involvement of a mitochondrial-dependent step to eventually elicit cell death, leading to the loss of mitochondrial membrane potential, cy- tochrome c release and the triggering of cell death. The overexpression of Bcl-2 or Bcl-xL blocks edelfosine-induced apoptosis. Edelfosine induces the redistribution of lipid rafts from the plasma Citation: Mollinedo, F.; Gajate, C. membrane to the mitochondria. The pro-apoptotic action of edelfosine on cancer cells is associated Mitochondrial Targeting Involving with the recruitment of F1FO–ATP synthase into cholesterol-rich lipid rafts. Specific inhibition of the Cholesterol-Rich Lipid Rafts in the F sector of the F F –ATP synthase, which contains the membrane-embedded c-subunit ring that Mechanism of Action of the O 1 O Antitumor Ether Lipid and constitutes the mitochondrial permeability transcription pore, hinders edelfosine-induced cell death.
    [Show full text]