DOCSLIB.ORG

ASPP2 Inhibits Tumor Growth by Repressing the Mevalonate Pathway

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
ASPP2 Inhibits Tumor Growth by Repressing the Mevalonate Pathway Liang et al. Cell Death and Disease (2019) 10:830 https://doi.org/10.1038/s41419-019-2054-7 Cell Death & Disease ARTICLE Open Access ASPP2 inhibits tumor growth by repressing the mevalonate pathway in hepatocellular carcinoma Beibei Liang1,RuiChen2, Shaohua Song3,HaoWang4,GuoweiSun5, Hao Yang1,WeiJing6, Xuyu Zhou6,ZhirenFu3, Gang Huang1 and Jian Zhao1 Abstract Cancer is, fundamentally, a disorder of cell growth and proliferation, which requires adequate supplies of energy and nutrients. In this study, we report that the haplo-insufficient tumor suppressor ASPP2, a p53 activator, negatively regulates the mevalonate pathway to mediate its inhibitory effect on tumor growth in hepatocellular carcinoma (HCC). Gene expression profile analysis revealed that the expression of key enzymes in the mevalonate pathway were increased when ASPP2 was downregulated. HCC cells gained higher cholesterol levels and enhanced tumor-initiating capability in response to the depletion of ASPP2. Simvastatin, a mevalonate pathway inhibitor, efficiently abrogated ASPP2 depletion-induced anchorage-independent cell proliferation, resistance to chemotherapy drugs in vitro, and tumor growth in xenografted nude mice. Mechanistically, ASPP2 interacts with SREBP-2 in the nucleus and restricts the transcriptional activity of SREBP-2 on its target genes, which include key enzymes involved in the mevalonate pathway. Moreover, clinical data revealed better prognosis in patients with high levels of ASPP2 and low levels of the mevalonate pathway enzyme HMGCR. Our findings provide functional and mechanistic insights into the critical role of ASPP2 in the regulation of the mevalonate pathway and the importance of this pathway in tumor initiation and tumor growth, which may provide a new therapeutic opportunity for HCC. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction development4. The mevalonate pathway (MVA) is the Dysregulation of a wide range of metabolic pathways essential metabolic pathway that converts acetyl-CoA to can be involved in carcinogenesis1. For example, choles- sterols such as cholesterol and non-sterol isoprenoids. terol has a critical role in maintaining the stability and Clinical and experimental findings suggest that malignant architecture of the plasma membrane and is needed by cells and tissues need higher amounts of cholesterol and highly proliferative cancer cells2. Tumor cell membranes intermediates of the mevalonate pathway than their nor- have been found to be enriched in cholesterol, suggesting mal counterparts5,6. Some types of cancers, such as that enhanced cholesterol utilization is an important hepatocellular carcinoma (HCC), depend on mevalonate feature of malignant and perhaps metastatic tumors3. pathway for growth. For example, inhibition of mevalo- Mutational data from The Cancer Genome Atlas (TCGA) nate metabolism suppresses tumor initiation and growth project also implicates cholesterol metabolism in cancer in a myc-transgenic murine HCC model7, activation of the mevalonate pathway also plays an essential role in liver tumorigenesis caused by p53 loss in mice8. Correspondence: Gang Huang ([email protected])or The mevalonate pathway is tightly regulated by a series Jian Zhao ([email protected]) of enzymes. 3-hydroxy-3-methylglutaryl-CoA reductase 1Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, 201318 Shanghai, China (HMGCR) is the rate-limiting enzyme, and can be blocked 2Angecon Biotechnology Limited, 201318 Shanghai, China by statins9; indeed, such inhibition has antitumor effects Full list of author information is available at the end of the article. in multiple tumor types9. Clinical observations have These authors contributed equally: Beibei Liang, Rui Chen, Shaohua Song, Hao Wang Edited by: A. Finazzi-Agrò © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association Liang et al. Cell Death and Disease (2019) 10:830 Page 2 of 11 shown a negative association between the use of statins However, it remains unknown whether ASPP2 is involved and the risk of developing liver cancer10. in the regulation of mevalonate metabolism, which may Transcriptional activation of key rate limiting enzymes, contribute to its inhibitory effect on tumor progression. In like HMGCR, in mevalonate pathway is controlled by this study, we provide evidence that downregulation of sterol-regulated cleavage of the membrane-bound tran- ASPP2 enhances tumor-initiating capabilities and tumor scription factor SREBP-2 (sterol regulated element bind- growth by promoting mevalonate metabolism in HCC. – ing protein-2)11 13. Depletion of intracellular sterols enhances SREBP-2 translocation from the endoplasmic Results reticulum (ER) to the Golgi apparatus, leading to sub- Downregulation of ASPP2 enhances mevalonate pathway sequent cleavage to its active mature form and nuclear gene expression and cholesterol biosynthesis in HCC cells translocation14. SREBP-2 binds to sterol regulatory ele- To explore the mechanisms driving the inhibitory ments (SREs) in its target gene promoters to activate their effects of ASPP2 on tumor growth and progression, we transcription. performed a microarray analysis to identify the potential ASPP2 is a member of the ankyrin-repeat, SH3-domain, down-stream targets of ASPP2 by comparing gene and proline-rich region-containing protein (ASPP) family, expression in ASPP2-depleted HCC-LM3 cells and parent and is a haplo-insufficient tumor suppressor15,16. Aber- cells. Interestingly, GO analysis revealed a significant rant expression of ASPP2 has been found in various negative correlation between ASPP2 expression and ter- human cancers17. Our previous study found that ASPP2 is penoid backbone biosynthesis and steroid biosynthesis downregulated by DNA methylation in HCC18. ASPP2 (Fig. 1a). Expression of genes involved in mevalonate inhibits tumor growth and metastasis through regulation pathway, such as Hmgcs1, Hmgcr, Mvk, Mvd, and Idi1, – of apoptosis, autophagy, and epithelial plasticity16,19 21. appeared to be significantly enriched (P < 0.05, FDR < Fig. 1 Downregulation of ASPP2 enhances mevalonate pathway gene expression and cholesterol biosynthesis in HCC cells. a Top: KEGG Pathway analysis of ASPP2 knockdown show significant differential changes (P < 0.05) in canonical metabolic pathways. The P value for each pathway is indicated by the bar and is expressed as −1 times the log of the P value. Arrows are used to indicated the two pathways closely related with mevalonate metabolism. Bottom: Gene Ontology (GO) analysis revealed genes were most significantly upregulated and enriched by ASPP2 knockdown in the terpenoid backbone biosynthesis pathway (P < 0.05, FDR < 0.25). b Schematic of the mevalonate pathway with asterisk (*) marking upregulated genes by ASPP2 knockdown in panel (a) bottom. c qRT-PCR of Hmgcs1, Hmgcr mRNA expression in HCC-LM3 and HepG2 cells infected with lentivirus encoding shRNA was indicated for 72 h. β-actin was used as a control. d Corresponding western-blot of HMGCS1 and HMGCR in HCC- LM3 and HepG2 cells. e Total cholesterol and free cholesterol were measured by GC-MS methods, using the internal standard strategy as methods described. Each symbol represents the mean ± SD of three wells. Asterisk (*) indicates P < 0.05 Official journal of the Cell Death Differentiation Association Liang et al. Cell Death and Disease (2019) 10:830 Page 3 of 11 Fig. 2 Mevalonate metabolism is essential for maintaining tumor-initiating capability in ASPP2-depleted HCC cells. a Top: Representative images of spheroid formation in HCC-LM3 cells treated with 0.01 μM simvastatin or DMSO after knock down of ASPP2. Bottom: the number of spheres formation per 1000 HCC-LM3 cells.Scale bar, 100 mm. b qRT-PCR gene expression of Aspp2, Oct-4, Ck-19, and Abcg2 in HCC-LM3 and HepG2 cells transfected with the indicated lentivirus and treated with 10 μM simvastatin or DMSO. c Immunofluorescence stainings of HCC-LM3 spheres formed from cells transfected with the indicated lentivirus and treated with 10 μM simvastatin or DMSO. Green staining represented EpCAM protein. DAPI was used stain nuclear(blue staining) Scale bar, 40 mm d Cell viability of the infected HCC-LM3 and HepG2 cell treated with 10 μM simvastatin or DMSO and 5-FU(0.6 mM,2.5 mM or 10 mM) was analyzed by MTS assay. Asterisk (*) indicates P < 0.05, asterisks (**) indicates P < 0.01 0.25) in ASPP2-depleted HCC-LM3 cells (Fig. 1b). To cell-like properties27. To verify the importance of meva- validate this finding, we examined the expression of lonate metabolism in ASPP2-depletion induced tumor- HMG-CoA reductase (HMGCR) and HMG-CoA syn- initiating capability in HCC cells,
Load more

Recommended publications
  • Of Mevalonate Metabolism'
    ICANCER RESEARCH57. 3498—3505.AugustIS. 9971 Regulation of Proliferation and Ras Localization in Transformed Cells by Products of Mevalonate Metabolism' Jennifer A. Cuthbert2 and Peter E. Lipsky Department of Internal Medicine. The Unit'ersitv of Texas Southwestern Medical (‘enterat Dallas. Dallas. Texas 75235-9151 ABSTRACT position 186, the removal of the three COOH-terminal amino acids at positions 187—189, and carboxymethylation of the new COOH-termi Lovastatin, an inhibitor of 3-hydroxy.3-methylglutaryl (HMG) CoA nab cysteine. In addition, either palmitybation of other cysteine resi reductase, and 6-fluoromevalonate (Fmev), an inhibitor of diphospho dues in the COOH terminus (H-Ras, N-Ras, and K-RasA) or a mevalonate decarboxylase, blocked the synthesis of downstream meval. onate products, including prenyl-derived lipids, and prevented membrane pobybasic domain (K-RasB) is important in enhancing membrane localization of Ras in the myeloid cell line U.937. In contrast to lovastatin, association (7). These processes occur stepwise, and the first step, that which induced cytosol localization of Ras in U-937 cells, Fmev failed to of farnesybation of the full-length polypeptide, is thereby essential for increase cytosolic Ras and also completely prevented the proliferation of plasma membrane localization (12—14).Thus, compounds and muta U.937 cells. Growth of U-937 cells was restored by the addition of lovas tions that block the process of farnesylation interfere with the trans tatin to Fmev-blocked cells. These results implied that a product of formation and proliferation that are dependent upon mutationally mevalonate metabolism proximal to isopentenyl diphosphate was respon. activated Ras.
    [Show full text]
  • 33 34 35 Lipid Synthesis Laptop
    BI/CH 422/622 Liver cytosol ANABOLISM OUTLINE: Photosynthesis Carbohydrate Biosynthesis in Animals Biosynthesis of Fatty Acids and Lipids Fatty Acids Triacylglycerides contrasts Membrane lipids location & transport Glycerophospholipids Synthesis Sphingolipids acetyl-CoA carboxylase Isoprene lipids: fatty acid synthase Ketone Bodies ACP priming 4 steps Cholesterol Control of fatty acid metabolism isoprene synth. ACC Joining Reciprocal control of b-ox Cholesterol Synth. Diversification of fatty acids Fates Eicosanoids Cholesterol esters Bile acids Prostaglandins,Thromboxanes, Steroid Hormones and Leukotrienes Metabolism & transport Control ANABOLISM II: Biosynthesis of Fatty Acids & Lipids Lipid Fat Biosynthesis Catabolism Fatty Acid Fatty Acid Synthesis Degradation Ketone body Utilization Isoprene Biosynthesis 1 Cholesterol and Steroid Biosynthesis mevalonate kinase Mevalonate to Activated Isoprenes • Two phosphates are transferred stepwise from ATP to mevalonate. • A third phosphate from ATP is added at the hydroxyl, followed by decarboxylation and elimination catalyzed by pyrophospho- mevalonate decarboxylase creates a pyrophosphorylated 5-C product: D3-isopentyl pyrophosphate (IPP) (isoprene). • Isomerization to a second isoprene dimethylallylpyrophosphate (DMAPP) gives two activated isoprene IPP compounds that act as precursors for D3-isopentyl pyrophosphate Isopentyl-D-pyrophosphate all of the other lipids in this class isomerase DMAPP Cholesterol and Steroid Biosynthesis mevalonate kinase Mevalonate to Activated Isoprenes • Two phosphates
    [Show full text]
  • Construction and Optimization of Mevalonate Pathway for Production Of
    Construction and Optimization of Mevalonate Pathway for Production of Isoprenoids in Escherichia coli by Farnaz Nowroozi A dissertation submitted in partial satisfaction of the requirements for the degree of Joint Doctor of Philosophy with University of California, San Francisco in Engineering-Bioengineering in the Graduate Division of the University of California, Berkeley Committee in charge: Professor Jay D. Keasling, Chair Professor Adam P. Arkin Professor Francis C. Szoka Professor Marc K. Hellerstein Fall 2009 1 The dissertation of Farnaz Foroughi-Boroujeni Nowroozi, titled Construction and Optimization of Mevalonate Pathway for production of Isoprenoids in Escherichia coli , is approved: Chair _______________________________ Date ____________________ _______________________________ Date____________________ _______________________________ Date ____________________ _______________________________ Date ____________________ University of California, Berkeley 2 Abstract Construction and Optimization of Mevalonate Pathway for production of Isoprenoids in Escherichia coli by Farnaz Foroughi-Boroujeni Nowroozi Doctor of Philosophy in Bioengineering University of California, Berkeley Professor Jay D. Keasling, Chair The isoprenoid family, containing over 50,000 members, constitutes one of the most structurally diverse groups of natural products. They range from essential and relatively universal primary metabolites, such as sterols, carotenoids, and hormones, to more unique secondary metabolites that serve roles in plant defense and communication and cellular and organismal development. Although these molecules have vast potential in medicine and industry their production is limited by two factors: 1- The yields from harvest and extraction of these compounds from their native sources are low 2- Due to their complex structure, synthetic routes to most isoprenoids are difficult and inefficient Therefore engineering metabolic pathways for production of large quantities of isoprenoids in a microbial host is an attractive approach.
    [Show full text]
  • Engineering a Mevalonate Pathway in Escherichia Coli for Production of Terpenoids
    ARTICLES Engineering a mevalonate pathway in Escherichia coli for production of terpenoids Vincent JJ Martin1,2,3, Douglas J Pitera1,3,Sydnor T Withers1,Jack D Newman1 & Jay D Keasling1 Isoprenoids are the most numerous and structurally diverse family of natural products. Terpenoids, a class of isoprenoids often isolated from plants, are used as commercial flavor and fragrance compounds and antimalarial or anticancer drugs. Because plant tissue extractions typically yield low terpenoid concentrations, we sought an alternative method to produce high-value terpenoid compounds, such as the antimalarial drug artemisinin, in a microbial host. We engineered the expression of a synthetic amorpha-4,11-diene synthase gene and the mevalonate isoprenoid pathway from Saccharomyces cerevisiae in Escherichia coli. Concentrations of amorphadiene, the sesquiterpene olefin precursor to artemisinin, reached 24 µg caryophyllene equivalent/ml. Because isopentenyl and dimethylallyl pyrophosphates are the universal precursors to all isoprenoids, the strains developed in this study can serve as platform hosts for the production of any terpenoid compound for which a terpene synthase gene is available. http://www.nature.com/naturebiotechnology Terpenoids comprise a highly diverse class of natural products from certain cancers10,11, and irufloven, a third-generation semisynthetic which numerous commercial flavors, fragrances and medicines are analog of the sesquiterpene illudin S that are in late-stage clinical derived. These valuable compounds are commonly isolated from trials for the treatment of various refractory and relapsed can- plants, microbes and marine organisms. For example, terpenoids cers12,13.In general, these drugs are extracted from the host plant, in extracted from plants are used as anticancer and antimalarial which they accumulate in very small amounts, before further drugs1,2.Because these compounds are naturally produced in small derivatization or use.
    [Show full text]
  • Evolution of Carotenoid and Isoprenoid Biosynthesis in Photosynthetic and Non-Photosynthetic Organisms
    EVOLUTION OF CAROTENOID AND ISOPRENOID BIOSYNTHESIS IN PHOTOSYNTHETIC AND NON-PHOTOSYNTHETIC ORGANISMS HARTMUT K. LICHTENTHALER Botanisches Institut II, University of Karlsruhe, Kaiserstr. 12, D-76128 Karlsruhe, Germany Email: [email protected] Abstract Sterols and carotenoids are typical representatives of the group of isoprenoid lipids in plants. All isoprenoids are synthesized by condensation of the two active C5-units: dimethylallyl diphosphate, DMAPP, and isopentenyl diphosphate, IPP. Like animals, higher plants form their sterols via the classical cytosolic acetate/mevalonate (MVA) pathway of IPP biosynthesis. Plants as photosynthetic organisms, however possess a second, non- mevalonate pathway for IPP biosynthesis, the DOXP/MEP pathway. The latter operates in the chloroplasts and is responsible for the formation of carotenoids and all other plastidic isoprenoid lipids (phytol, prenylquinones). Although there exists some cooperation between both IPP producing pathways, one can never fully compensate for the other. Thus, in higher plants sterols are primarily made via the MVA pathway and carotenoids via the DOXP pathway. This also applies to several algae groups, such as red algae and Heterokontophyta. In the large and diverging group of 'Green Algae' the situation is more complex. The more advanced evolutionary groups (Charales, Zygnematales) possess, like higher plants, both IPP forming pathways and represent an evolutionary link to these. In contrast, the proper Chlorophyta, often single cell organisms (Chlorella, Scenedesmus, Trebouxia), represent a separate phylum and synthesize sterols and carotenoids via the DOXP pathway whereas the MVA pathway is lost. The common ancestor of both groups, Mesostigma viride, again exhibits both IPP pathways. In the photosynthetic Euglenophyta the situation is inverse, both the sterols and the carotenoids are formed exclusively via the MVA pathway, the DOXP pathway is lost during the secondary endosymbiosis.
    [Show full text]
  • Controlled Sumoylation of the Mevalonate Pathway Enzyme HMGS-1 Regulates Metabolism During Aging
    Controlled sumoylation of the mevalonate pathway enzyme HMGS-1 regulates metabolism during aging Amir Sapira,b, Assaf Tsurc, Thijs Koormand, Kaitlin Chinga,b, Prashant Mishraa, Annabelle Bardenheiera,b, Lisa Podolskyc, Ulrike Bening-Abu-Shachc, Mike Boxemd, Tsui-Fen Choue, Limor Brodayc,1, and Paul W. Sternberga,b,1 aDivision of Biology and Biological Engineering and bHoward Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125; cDepartment of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; dDevelopmental Biology, Utrecht University, 3584 CH, Utrecht, The Netherlands; and eDivision of Medical Genetics, Department of Pediatrics, and Los Angeles Biomedical Research Institute, Harbor–UCLA Medical Center, Torrance, CA 90502 Contributed by Paul W. Sternberg, August 6, 2014 (sent for review July 3, 2014) Many metabolic pathways are critically regulated during develop- Many cellular processes and physiological states rely on vari- ment and aging but little is known about the molecular mecha- able levels of mevalonate pathway metabolites, suggesting that nisms underlying this regulation. One key metabolic cascade in the pathway activity is highly regulated during the organism’s life eukaryotes is the mevalonate pathway. It catalyzes the synthesis of cycle. Elucidating the molecular details of this regulation is the sterol and nonsterol isoprenoids, such as cholesterol and ubiqui- first step in understanding how pathway dysregulation leads to none, as well as other metabolites. In humans, an age-dependent diseases. For example, as part of the tumorigenic process of decrease in ubiquinone levels and changes in cholesterol homeo- breast cancer cells, the expression of many mevalonate pathway stasis suggest that mevalonate pathway activity changes with age.
    [Show full text]
  • Mevalonate and Nonmevalonate Pathways for the Biosynthesis of Isoprene Units
    Biosci. Biotechnol. Biochem., 66 (8), 1619–1627, 2002 Review Mevalonate and Nonmevalonate Pathways for the Biosynthesis of Isoprene Units Tomohisa KUZUYAMA Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan Isoprenoids are synthesized by consecutive condensa- nate pathway in humans. Its speciˆc inhibitors, tions of their ˆve-carbon precursor, isopentenyl pravastatin and related compounds, are widely used diphosphate, to its isomer, dimethylallyl diphosphate. as cholesterol-lowering agents.6) Mevalonate is then Two pathways for these precursors are known. One is phosphorylated twice and decarboxylated to form the mevalonate pathway, which operates in eucaryotes, isopentenyl diphosphate (IPP). IPP is then converted archaebacteria, and cytosols of higher plants. The other to its isomer, dimethylallyl diphosphate (DMAPP), is a recently discovered pathway, the nonmevalonate catalyzed by IPP isomerase. IPP and DMAPP syn- pathway, which is used by many eubacteria, green thesized in the mevalonate pathway are used as basic algae, and chloroplasts of higher plants. To date, ˆve units in the biosynthesis of isoprenoids such as reaction steps in this new pathway and their corre- sterols, carotenoids, and dolichols. sponding enzymes have been identiˆed. EC numbers of Since the discovery of the mevalonate pathway, it these enzymes have been assigned by the Nomenclature was widely accepted that IPP and DMAPP were Committee of the International Union of Biochemistry formed only through this pathway in all living organ- and Molecular Biology (NC-IUBMB) and are available isms. However, several results inconsistent with the at http:WWwww.chem.qmw.ac.ukWiubmbWenzymeWreac- operation of the mevalonate pathway in certain bac- 13 tionWterpWnonMVA.html.
    [Show full text]
  • Disorder of the Mevalonate Pathway Inhibits Calcium‑Induced Differentiation of Keratinocytes
    MOLECULAR MEDICINE REPORTS 16: 4811-4816, 2017 Disorder of the mevalonate pathway inhibits calcium‑induced differentiation of keratinocytes RUI JIN1, XIN LUO1, KANG LUAN1, LI LIU1, LIANG-DAN SUN2, SEN YANG2, SHENG-QUAN ZHANG1,2 and XUE-JUN ZHANG2 1Department of Biochemistry and Molecular Biology; 2Department of Dermatology, Institute of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui 230022, P.R. China Received January 22, 2016; Accepted March 3, 2017 DOI: 10.3892/mmr.2017.7128 Abstract. Mutation of genes encoding the enzymes of the Introduction mevalonate pathway cause a variety of diseases, including skin disorders. Mutation of four genes in this pathway, including The mevalonate metabolic pathway serves a key role in mevalonate kinase, phosphomevalonate kinase, mevalonate cellular processes, including proliferation, differentiation and diphosphate decarboxylase and farnesyl diphosphate synthase, apoptosis (1-3). Dysregulation of the pathway may lead to the have demonstrated to be responsible for porokeratosis (PK). development of diseases including cancer and cardiovascular However, the pathogenesis of PK remains unclear. In the disease (4,5). Components of this pathway include mevalonic present study, specific enzyme inhibitors of the mevalonate acid (MVA), isopentenyl pyrophosphate (IPP), ubiquinone pathway, including pravastatin (PRA), alendronate (ALD), (CoQ), farnesyl pyrophosphate (FPP), geranylgeranyl pyro- farnesyl transferase inhibitor (FTI-277) and geranylgeranyl phosphate, cholesterol(CH) and heme A (Fig. 1A) (6,7). It has transferase inhibitor (GGTI-298), were used to investigate been reported that mutation of genes coding for the enzymes the effect on differentiation of keratinocytes (KCs). Western in this pathway may lead to monogenic inherited diseases, blotting demonstrated that PRA, ALD, FTI-277 or GGTI-298 including hyperimmunoglobulinemia D syndrome (HIDS) alone, or in combination, inhibited the expression level of and porokeratosis (PK).
    [Show full text]
  • Molecular Atlas of Postnatal Mouse Heart Development
    bioRxiv preprint doi: https://doi.org/10.1101/302802; this version posted April 23, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Talman, Teppo, Pöhö et al. Molecular atlas of postnatal mouse heart development Virpi Talman PhD1*, Jaakko Teppo MSc2,3*, Päivi Pöhö MSc2*, Parisa Movahedi MSc4, Anu Vaikkinen PhD2, S. Tuuli Karhu MSc1, Kajetan Trošt PhD5, Tommi Suvitaival PhD5, Jukka Heikkonen PhD4, Tapio Pahikkala PhD4, Tapio Kotiaho PhD2,6, Risto Kostiainen PhD2#, Markku Varjosalo PhD3#, Heikki Ruskoaho MD, PhD1# 1Drug Research Program and Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, FINLAND 2 Drug Research Program and Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, FINLAND 3 Institute of Biotechnology and HiLIFE Helsinki Institute of Life Science, University of Helsinki, FI-00014 Helsinki, FINLAND 4 Department of Future Technologies, Faculty of Mathematics and Natural Sciences, University of Turku, FI-20500 Turku, FINLAND 5 Steno Diabetes Center Copenhagen, DK-2820 Gentofte, DENMARK 6 Department of Chemistry, Faculty of Science, University of Helsinki, FI-00014 Helsinki, FINLAND * Equal contribution # Correspondence to: Heikki Ruskoaho, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, FI-00014 Helsinki, FINLAND. [email protected] or Markku Varjosalo PhD, Institute of Biotechnology and HiLIFE Helsinki Institute of Life Science, University of Helsinki, P.O. Box 65, FI-00014 Helsinki, FINLAND [email protected] or Risto Kostiainen PhD, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O.
    [Show full text]
  • Mevalonate Pathway Provides Ubiquinone to Maintain Pyrimidine
    Author Manuscript Published OnlineFirst on November 19, 2019; DOI: 10.1158/0008-5472.CAN-19-0650 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Mevalonate pathway provides ubiquinone to maintain pyrimidine 2 synthesis and survival in p53-deficient cancer cells exposed to metabolic 3 stress 4 5 Irem, Kaymak1, Carina, R., Maier1, Werner, Schmitz1, Andrew, D., Campbell2, 6 Beatrice, Dankworth1, Carsten, P., Ade1, Susanne, Walz3, Madelon, Paauwe2, 7 Charis, Kalogirou4, Hecham, Marouf1, Mathias, T., Rosenfeldt5,6, David, M., 8 Gay2,7, Grace, H., McGregor2,7, Owen, J., Sansom2 and Almut, Schulze1,6$# 9 10 1 Theodor-Boveri-Institute, Biocenter, Am Hubland, 97074 Würzburg, Germany 11 2 Cancer Research UK Beatson Institute, Garscube Estate Switchback Road 12 Bearsden Glasgow, G61 1BD 13 3 ComPrehensive Cancer Center Mainfranken, Core Unit Bioinformatics, 14 Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany 15 4 DePartment of Urology, University Hospital Würzburg, Josef-Schneider-Str. 2, 16 97080 Würzburg 17 5 DePartment of Pathology, University HosPital Würzburg, Josef-Schneider-Str. 18 2, 97080 Würzburg 19 6 ComPrehensive Cancer Center Mainfranken, Josef-Schneider-Str.6, 97080 20 Würzburg, Germany 21 7Institute of Cancer Sciences, University of Glasgow, Garscube Estate, 22 Switchback Road, Bearsden, Glasgow, G61 1QH 23 24 #Corresponding author 25 email: [email protected] 26 $Current address: Division of Tumor Metabolism and Microenvironment, 27 German Cancer Research Center, Im Neuenheimer Feld 281, 69120 28 Heidelberg, Germany ([email protected]) 29 Phone: +49 6221 42 3423 30 31 Running Title: Mevalonate pathway supports ubiquinone synthesis in cancer 32 Conflict of interest: The authors declare no competing financial interests.
    [Show full text]
  • Increased Sensitivity of Multidrug-Resistant Myeloid Leukemia Cell Lines to Lovastatin L Maksumova, K Ohnishi, F Muratkhodjaev, W Zhang, L Pan, a Takeshita and R Ohno
    Leukemia (2000) 14, 1444–1450 2000 Macmillan Publishers Ltd All rights reserved 0887-6924/00 $15.00 www.nature.com/leu Increased sensitivity of multidrug-resistant myeloid leukemia cell lines to lovastatin L Maksumova, K Ohnishi, F Muratkhodjaev, W Zhang, L Pan, A Takeshita and R Ohno Department of Medicine III, Hamamatsu University School of Medicine, 3600, Handa-cho, Hamamatsu, 431-3192, Japan Lovastatin, a competitive inhibitor of HMG-CoA reductase, inhibitor of neoplastic cell proliferation and a powerful reportedly inhibits proliferation and induces apoptosis of tumor inducer of apoptosis and cell cycle alterations (G0/G1 cell cells with MDR-1 coded P-glycoprotein (Pgp) expression. In 8–11 this study we investigated the sensitivity to lovastatin of eight cycle phase block) in various tumor cell lines. Moreover, myeloid leukemia cell lines: K562, NOMO-1, NB4 and its retinoic lovastatin has been reported to preferentially target multidrug- acid (RA) resistant subline NB4/RA, and their multidrug-resist- resistant neoplastic cells in myeloma,12 breast carcinoma13 ant (MDR) sublines: K562/ADR, NOMO-1/ADR, NB4/MDR and and neuroblastoma14 compared with their parental drug-sensi- NB4/RA/MDR. MTT and apoptosis assays revealed that K- tive cells in vitro. As for leukemia cell lines, a human multi- 562/ADR, NOMO-1/ADR and NB4/RA/MDR were more sensitive drug-resistant myeloid leukemia cell line, HL-60/VCR, was to lovastatin than their parental cell lines, while NB4/MDR 15 showed the same level of sensitivity as parental NB4 cells, recently shown to be equally sensitive to lovastatin, suggest- which already were very sensitive to lovastatin.
    [Show full text]
  • The Mevalonate Pathway Contributes to Monoterpene Production in Peppermint
    bioRxiv preprint doi: https://doi.org/10.1101/2020.05.29.124016; this version posted May 31, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 TITLE 2 The mevalonate pathway contributes to monoterpene production in peppermint 3 Short title: Crosstalk of MVA and MEP by MFA of trichome cells 4 Authors: 5 Somnath Koley1,2, Eva Grafahrend-Belau1, Manish L. Raorane1, Björn H. Junker1* 6 *correspondence: [email protected] 7 Authors’ information: 8 Somnath Koley 9 Email: [email protected] 10 Orcid ID: 0000-0002-5385-3395 11 Dr. Eva Grafahrend-Belau 12 Email: [email protected] 13 Orcid ID: 0000-0002-1938-3908 14 Dr. Manish L. Raorane 15 Email: [email protected] 16 Orcid ID: 0000-0002-7729-7362 17 Prof. Dr. Björn H. Junker 18 Email: [email protected] 19 Orcid ID: 0000-0001-5818-9764 20 Address1: 21 Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany. 22 Address2 (present address of the first author): 23 Donald Danforth Plant Science Center, Saint Louis, Missouri, United States Of America. 24 Materials Distribution: 25 The author responsible for distribution of materials integral to the findings presented in this 26 article in accordance with the policy described in the Instructions for Authors 27 (www.plantcell.org) is: Björn H. Junker ([email protected]). 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.05.29.124016; this version posted May 31, 2020.
    [Show full text]