Bioactive Ether Lipids: Primordial Modulators of Cellular Signaling
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Lipid Raft-Mediated Akt Signaling As a Therapeutic Target in Mantle Cell Lymphoma
OPEN Citation: Blood Cancer Journal (2013) 3, e118; doi:10.1038/bcj.2013.15 & 2013 Macmillan Publishers Limited All rights reserved 2044-5385/13 www.nature.com/bcj ORIGINAL ARTICLE Lipid raft-mediated Akt signaling as a therapeutic target in mantle cell lymphoma M Reis-Sobreiro1, G Roue´ 2, A Moros2, C Gajate1, J de la Iglesia-Vicente1, D Colomer2 and F Mollinedo1 Recent evidence shows that lipid raft membrane domains modulate both cell survival and death. Here, we have found that the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway is present in the lipid rafts of mantle cell lymphoma (MCL) cells, and this location seems to be critical for full activation and MCL cell survival. The antitumor lipids (ATLs) edelfosine and perifosine target rafts, and we found that ATLs exerted in vitro and in vivo antitumor activity against MCL cells by displacing Akt as well as key regulatory kinases p-PDK1 (phosphatidylinositol-dependent protein kinase 1), PI3K and mTOR (mammalian TOR) from lipid rafts. This raft reorganization led to Akt dephosphorylation, while proapoptotic Fas/CD95 death receptor was recruited into rafts. Raft integrity was critical for Ser473 Akt phosphorylation. ATL-induced apoptosis appeared to correlate with the basal Akt phosphorylation status in MCL cell lines and primary cultures, and could be potentiated by the PI3K inhibitor wortmannin, or inhibited by the Akt activator pervanadate. Classical Akt inhibitors induced apoptosis in MCL cells. Microenvironmental stimuli, such as CD40 ligation or stromal cell contact, did not prevent ATL-induced apoptosis in MCL cell lines and patient-derived cells. These results highlight the role of raft-mediated PI3K/Akt signaling in MCL cell survival and chemotherapy, thus becoming a new target for MCL treatment. -
Lysophosphatidic Acid and Its Receptors: Pharmacology and Therapeutic Potential in Atherosclerosis and Vascular Disease
JPT-107404; No of Pages 13 Pharmacology & Therapeutics xxx (2019) xxx Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Lysophosphatidic acid and its receptors: pharmacology and therapeutic potential in atherosclerosis and vascular disease Ying Zhou a, Peter J. Little a,b, Hang T. Ta a,c, Suowen Xu d, Danielle Kamato a,b,⁎ a School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD 4102, Australia b Department of Pharmacy, Xinhua College of Sun Yat-sen University, Tianhe District, Guangzhou 510520, China c Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, St Lucia, QLD 4072, Australia d Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA article info abstract Available online xxxx Lysophosphatidic acid (LPA) is a collective name for a set of bioactive lipid species. Via six widely distributed G protein-coupled receptors (GPCRs), LPA elicits a plethora of biological responses, contributing to inflammation, Keywords: thrombosis and atherosclerosis. There have recently been considerable advances in GPCR signaling especially Lysophosphatidic acid recognition of the extended role for GPCR transactivation of tyrosine and serine/threonine kinase growth factor G-protein coupled receptors receptors. This review covers LPA signaling pathways in the light of new information. The use of transgenic and Atherosclerosis gene knockout animals, gene manipulated cells, pharmacological LPA receptor agonists and antagonists have Gproteins fi β-arrestins provided many insights into the biological signi cance of LPA and individual LPA receptors in the progression Transactivation of atherosclerosis and vascular diseases. -
(4,5) Bisphosphate-Phospholipase C Resynthesis Cycle: Pitps Bridge the ER-PM GAP
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by UCL Discovery Topological organisation of the phosphatidylinositol (4,5) bisphosphate-phospholipase C resynthesis cycle: PITPs bridge the ER-PM GAP Shamshad Cockcroft and Padinjat Raghu* Dept. of Neuroscience, Physiology and Pharmacology, Division of Biosciences, University College London, London WC1E 6JJ, UK; *National Centre for Biological Sciences, TIFR-GKVK Campus, Bellary Road, Bangalore 560065, India Address correspondence to: Shamshad Cockcroft, University College London UK; Phone: 0044-20-7679-6259; Email: [email protected] Abstract Phospholipase C (PLC) is a receptor-regulated enzyme that hydrolyses phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) at the plasma membrane (PM) triggering three biochemical consequences, the generation of soluble inositol 1,4,5-trisphosphate (IP3), membrane– associated diacylglycerol (DG) and the consumption of plasma membrane PI(4,5)P2. Each of these three signals triggers multiple molecular processes impacting key cellular properties. The activation of PLC also triggers a sequence of biochemical reactions, collectively referred to as the PI(4,5)P2 cycle that culminates in the resynthesis of this lipid. The biochemical intermediates of this cycle and the enzymes that mediate these reactions are topologically distributed across two membrane compartments, the PM and the endoplasmic reticulum (ER). At the plasma membrane, the DG formed during PLC activation is rapidly converted to phosphatidic acid (PA) that needs to be transported to the ER where the machinery for its conversion into PI is localised. Conversely, PI from the ER needs to be rapidly transferred to the plasma membrane where it can be phosphorylated by lipid kinases to regenerate PI(4,5)P2. -
Membrane Lipid Therapy: Modulation of the Cell Membrane Composition and Structure As a Molecular Base for Drug Discovery and New Disease Treatment
Progress in Lipid Research 59 (2015) 38–53 Contents lists available at ScienceDirect Progress in Lipid Research journal homepage: www.elsevier.com/locate/plipres Review Membrane lipid therapy: Modulation of the cell membrane composition and structure as a molecular base for drug discovery and new disease treatment Pablo V. Escribá a, Xavier Busquets a, Jin-ichi Inokuchi b, Gábor Balogh c, Zsolt Török c, Ibolya Horváth c, ⇑ ⇑ John L. Harwood d, , László Vígh c, a Department of Biology, University of the Balearic Islands, E-07122 Palma de Mallorca, Spain b Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University, Sendai, Japan c Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary d School of Biosciences, Cardiff University, Cardiff CF10 3AX, Wales, UK article info abstract Article history: Nowadays we understand cell membranes not as a simple double lipid layer but as a collection of Received 28 January 2015 complex and dynamic protein–lipid structures and microdomains that serve as functional platforms Received in revised form 10 April 2015 for interacting signaling lipids and proteins. Membrane lipids and lipid structures participate directly Accepted 29 April 2015 as messengers or regulators of signal transduction. In addition, protein–lipid interactions participate in Available online 9 May 2015 the localization of signaling protein partners to specific membrane microdomains. Thus, lipid alterations Dedicated to the memory of our late change cell signaling that are associated with a variety of diseases including cancer, obesity, neurodegen- colleague and friend, Professor John E. erative disorders, cardiovascular pathologies, etc. This article reviews the newly emerging field of mem- Halver. -
Lysophosphatidic Acid Signaling in the Nervous System
Neuron Review Lysophosphatidic Acid Signaling in the Nervous System Yun C. Yung,1,3 Nicole C. Stoddard,1,2,3 Hope Mirendil,1 and Jerold Chun1,* 1Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA 2Biomedical Sciences Graduate Program, University of California, San Diego School of Medicine, La Jolla, CA 92037, USA 3Co-first author *Correspondence: [email protected] http://dx.doi.org/10.1016/j.neuron.2015.01.009 The brain is composed of many lipids with varied forms that serve not only as structural components but also as essential signaling molecules. Lysophosphatidic acid (LPA) is an important bioactive lipid species that is part of the lysophospholipid (LP) family. LPA is primarily derived from membrane phospholipids and signals through six cognate G protein-coupled receptors (GPCRs), LPA1-6. These receptors are expressed on most cell types within central and peripheral nervous tissues and have been functionally linked to many neural pro- cesses and pathways. This Review covers a current understanding of LPA signaling in the nervous system, with particular focus on the relevance of LPA to both physiological and diseased states. Introduction LPA synthesis/degradative enzymes (reviewed in Sigal et al., The human brain is composed of approximately 60%–70% lipids 2005; Brindley and Pilquil, 2009; Perrakis and Moolenaar, by dry weight (Svennerholm et al., 1994). These lipids can be 2014). In view of the broad neurobiological influences of LPA divided into two major pools, structural and signaling, which signaling, its dysregulation may lead to diverse neuropathologies include well-known families such as cholesterol, fatty acids, ei- (Bandoh et al., 2000; Houben and Moolenaar, 2011; Yung et al., cosanoids, endocannabinoids, and prostaglandins (Figure 1). -
Targeting Lysophosphatidic Acid in Cancer: the Issues in Moving from Bench to Bedside
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by IUPUIScholarWorks cancers Review Targeting Lysophosphatidic Acid in Cancer: The Issues in Moving from Bench to Bedside Yan Xu Department of Obstetrics and Gynecology, Indiana University School of Medicine, 950 W. Walnut Street R2-E380, Indianapolis, IN 46202, USA; [email protected]; Tel.: +1-317-274-3972 Received: 28 August 2019; Accepted: 8 October 2019; Published: 10 October 2019 Abstract: Since the clear demonstration of lysophosphatidic acid (LPA)’s pathological roles in cancer in the mid-1990s, more than 1000 papers relating LPA to various types of cancer were published. Through these studies, LPA was established as a target for cancer. Although LPA-related inhibitors entered clinical trials for fibrosis, the concept of targeting LPA is yet to be moved to clinical cancer treatment. The major challenges that we are facing in moving LPA application from bench to bedside include the intrinsic and complicated metabolic, functional, and signaling properties of LPA, as well as technical issues, which are discussed in this review. Potential strategies and perspectives to improve the translational progress are suggested. Despite these challenges, we are optimistic that LPA blockage, particularly in combination with other agents, is on the horizon to be incorporated into clinical applications. Keywords: Autotaxin (ATX); ovarian cancer (OC); cancer stem cell (CSC); electrospray ionization tandem mass spectrometry (ESI-MS/MS); G-protein coupled receptor (GPCR); lipid phosphate phosphatase enzymes (LPPs); lysophosphatidic acid (LPA); phospholipase A2 enzymes (PLA2s); nuclear receptor peroxisome proliferator-activated receptor (PPAR); sphingosine-1 phosphate (S1P) 1. -
Epirubicin Enhances TRAIL-Induced Apoptosis in Gastric Cancer Cells by Promoting Death Receptor Clustering in Lipid Rafts
MOLECULAR MEDICINE REPORTS 4: 407-411, 2011 Epirubicin enhances TRAIL-induced apoptosis in gastric cancer cells by promoting death receptor clustering in lipid rafts LING XU, XIUJUAN QU, YING LUO, YE ZHANG, JING LIU, JINGLEI QU, LINGYUN ZHANG and YUNPENG LIU Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, P.R. China Received December 16, 2010; Accepted February 4, 2011 DOI: 10.3892/mmr.2011.439 Abstract. Gastric cancer cells are usually insensitive to tumor induce apoptosis in many cancer cells without causing signifi- necrosis factor-related apoptosis-inducing ligand (TRAIL). cant toxicity to normal cells. TRAIL triggers apoptosis upon In the present study, in MGC803 cells treated with 100 ng/ml engagement of two receptors named death receptor 4 (DR4) TRAIL for 24 h, the inhibition rate of cell proliferation was and death receptor 5 (DR5). In response to TRAIL, death 9.76±2.39% and the rate of cell apoptosis was only 4.37±1.45%. receptors recruit the Fas-associated death domain (FADD) Treatment with epirubicin (1.18 µg/ml, IC50 dose for 24 h) and and procaspase-8 and -10, hence forming the macromolecular TRAIL (100 ng/ml for 24 h) led to a marked increase in the complex, termed the death-inducing signaling complex (DISC). inhibition rate of cell proliferation and apoptosis compared to Within this complex, procaspase-8 and -10 are activated treatment with epirubicin or TRAIL alone (P<0.05). Moreover, and initiate the caspase cascade, leading to apoptosis (3,4). even more notable cleavage of caspase-3 and 8 was detected However, previous studies including our own have reported with the combination of epirubicin and TRAIL. -
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 LI phase as the sample hydrates at 20 C. -
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. -
Lipid Signaling in Cytosolic Phospholipase A2α– Cyclooxygenase-2 Cascade Mediates Cerebellar Long- Term Depression and Motor Learning
Lipid signaling in cytosolic phospholipase A2α– cyclooxygenase-2 cascade mediates cerebellar long- term depression and motor learning Tung Dinh Lea,1, Yoshinori Shiraia, Takehito Okamotob, Tetsuya Tatsukawab, Soichi Nagaob, Takao Shimizuc, and Masao Itoa,2 aIto Laboratory and bNagao Laboratory, RIKEN Brain Science Institute, Saitama 351-0198, Japan; and cDepartment of Biochemistry, Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan Contributed by Masao Ito, December 31, 2009 (sent for review June 30, 2009) In this study, we show the crucial roles of lipid signaling in long- surge, self-regeneration may develop by positive feedback through term depression (LTD), that is, synaptic plasticity prevailing in this closed loop, leading to a rapid, intense activation of PKCα that cerebellar Purkinje cells. In mouse brain slices, we found that switches the status of PF-AMPARs from a basal state to the per- cPLA2α knockout blocked LTD induction, which was rescued by sistently depressed state for LTD (8, 20). replenishing arachidonic acid (AA) or prostaglandin (PG) D2 or E2. In this study, we demonstrate the critical requirement of – Moreover, cyclooxygenase (COX) 2 inhibitors block LTD, which is cPLA2α-COX-2 cascade for LTD induction. Incorporating the rescued by supplementing PGD2/E2. The blockade or rescue occurs cascade and its downstream pathways, we modify the LTD- when these reagents are applied within a time window of 5–15 inducing signal transduction model (Fig. 1). Furthermore, to test min following the onset of LTD-inducing stimulation. Furthermore, the current hypothesis that LTD underlies motor learning, we PGD2/E2 facilitates the chemical induction of LTD by a PKC activa- examine whether the deficiency of cPLA2α or the i.p.admin- tor but is unable to rescue the LTD blocked by a PKC inhibitor. -
Phosphoinositide Phosphatase SHIP-1 Regulates Apoptosis Induced by Edelfosine, Fas Ligation and DNA Damage in Mouse Lymphoma Cells Maaike C
Phosphoinositide phosphatase SHIP-1 regulates apoptosis induced by edelfosine, Fas ligation and DNA damage in mouse lymphoma cells Maaike C. Alderliesten, Jeffrey B. Klarenbeek, Arnold H. van der Luit, Menno van Lummel, David R Jones, Shuraila Zerp, Nullin Divecha, Marcel Verheij, Wim J van Blitterswijk To cite this version: Maaike C. Alderliesten, Jeffrey B. Klarenbeek, Arnold H. van der Luit, Menno van Lummel, David R Jones, et al.. Phosphoinositide phosphatase SHIP-1 regulates apoptosis induced by edelfosine, Fas ligation and DNA damage in mouse lymphoma cells. Biochemical Journal, Portland Press, 2011, 440 (1), pp.127-135. 10.1042/BJ20110125. hal-00642836 HAL Id: hal-00642836 https://hal.archives-ouvertes.fr/hal-00642836 Submitted on 19 Nov 2011 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Biochemical Journal Immediate Publication. Published on 27 Jul 2011 as manuscript BJ20110125 Phosphoinositide phosphatase SHIP-1 regulates apoptosis induced by edelfosine, Fas ligation and DNA damage in mouse lymphoma cells Maaike C. ALDERLIESTEN*, Jeffrey B. KLARENBEEK*, Arnold H. VAN DER ‡ LUIT*2, Menno VAN LUMMEL*3, David R. JONES , Shuraila ZERP*†, Nullin ‡ DIVECHA , Marcel VERHEIJ† and Wim J. VAN BLITTERSWIJK*1 *Division of Cell Biology (B5) and †Department of Radiotherapy, The Netherlands Cancer Institute/ Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The ‡ Netherlands, Paterson Institute for Cancer Research, Inositide laboratory, The University of Manchester, Wilmslow Road, M20 4BX Manchester, UK. -
Akt Inhibitors in Cancer Treatment: the Long Journey from Drug Discovery to Clinical Use (Review)
INTERNATIONAL JOURNAL OF ONCOLOGY 48: 869-885, 2016 Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use (Review) GeORGe MIHAI NITUleSCU1, DeNISA MARGINA1, PeTRAS JUzeNAS2, QIAN PeNG2, OctavIAN TUDORel OlARU1, eMMANOUIl SAlOUSTROS3, CONCETTINA FENGA4, DeMeTRIOS Α. Spandidos5, MASSIMO lIBRA6 and ARISTIDIS M. Tsatsakis7 1Faculty of Pharmacy, ‘Carol Davila’ University of Medicine and Pharmacy, Bucharest 020956, Romania; 2Department of Pathology, Radiumhospitalet, Oslo University Hospital, 0379 Oslo, Norway; 3Oncology Unit, General Hospital of Heraklion ‘venizelio’, Heraklion 71409, Greece; 4Section of Occupational Medicine, University of Messina, I‑98125 Messina, Italy; 5Department of virology, Faculty of Medicine, University of Crete, Heraklion 71003, Greece; 6Department of Biomedical and Biotechnological Sciences, General and Clinical Pathology and Oncology Section, University of Catania, I‑95124 Catania, Italy; 7Department of Forensic Sciences and Toxicology, Faculty of Medicine, University of Crete, Heraklion 71003, Greece Received November 17, 2015; Accepted December 24, 2015 DOI: 10.3892/ijo.2015.3306 Abstract. Targeted cancer therapies are used to inhibit the importance of each chemical scaffold. We explore the pipeline growth, progression, and metastasis of the tumor by interfering of Akt inhibitors and their preclinical and clinical examina- with specific molecular targets and are currently the focus of tion status, presenting the potential clinical application of these anticancer drug development.