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Identification of autophagy-modulating natural products and derivatives for the elimination of therapy-resistant tumor cells Inaugural-Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf vorgelegt von Jana Deitersen aus Essen Düsseldorf, Mai 2020 aus dem Institut für Molekulare Medizin I der Heinrich-Heine-Universität Düsseldorf Gedruckt mit der Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf Referent: Univ.-Prof. Dr. Björn Stork Koreferent: Univ.-Prof. Dr. Peter Proksch Tag der mündlichen Prüfung in englischer Sprache: Eidesstattliche Erklärung Ich versichere an Eides statt, dass die Dissertation von mir selbständig und ohne unzulässige fremde Hilfe unter Beachtung der „Grundsätze zur Sicherung guter wissenschaftlicher Praxis an der Heinrich- Heine-Universität Düsseldorf“ erstellt worden ist. Die vorliegende Arbeit wurde von mir selbständig verfasst und keine anderen als die angegebenen Hilfsmittel verwendet. Alle wörtlich oder inhaltlich übernommenen Stellen habe ich als solche gekennzeichnet. Zudem versichere ich, dass ich die vorliegende Dissertation nur in diesem und keinem anderen Promotionsverfahren eingereicht habe und diesem kein früheres Promotionsverfahren vorausgegangen ist. ___________________________ ___________________ Ort, Datum Jana Deitersen ᳿㩤᳿ᴩ候≯ȼ Ein Schritt, ein Fußabdruck. Acknowledgement Mein besonderer Dank gilt meinem Doktorvater Prof. Dr. Björn Stork für die hervorragende fachliche Betreuung, angeregte Diskussionen und Anleitung zur wissenschaftlichen Selbstständigkeit. Jemanden zum Mentor zu haben, dessen geistige Wahlheimat Gelsenkirchen ist, hat mir meinen Ruhrpott ins Rheinland gebracht. Weiterhin danke ich meinem Zweitgutachter Prof. Peter Proksch für die Begutachtung dieser Arbeit und darüber hinaus für seine überragende Expertise auf dem Gebiet der Naturstoffe, seine chinesischen Kontakte und uneingeschränkte Passion für unsere gemeinsamen Kooperationsprojekte. Großer Dank gilt auch Prof. Sebastian Wesselborg, an dessen Institut für Molekulare Medizin I ich diese Arbeit angefertigt habe. Das wertvollste Inventar seines Instituts sind die Kolleginnen und Kollegen, die mir Wegbegleiter, Familienersatz und Freunde sind, und ohne diese die vorliegende Arbeit nicht möglich gewesen wäre. Danke, thank you, 嬡嬡, gracias! Diese Arbeit war ein Teilprojekt eines interdisziplinären Graduiertenkollegs, in welchem pharmazeutische, chemische, biologische und medizinische Expertise zusammengefunden hat. Daher möchte ich mich bei allen Kolleginnen und Kollegen des GRK2158, dessen Koordinatorin Martina Holz und der DFG für die Förderung bedanken. Weiterer Dank gilt allen Kooperationspartnern und Co- Autoren, welche in Abschnitt 4 ausdrücklich erwähnt werden. Mille grazie a Maria Chiara Monti e le sue ragazze per l'ospitalità, per darmi il benvenuto nel tuo laboratorio e famiglie. Grazie cucciolotte! Die Motivation für diese Doktorarbeit entstammt hauptsächlich einer inhärenten Neugier, für deren Förderung ich im Besonderen fähigen Professoren, Lehrern und Erziehern danken möchte. Ausschlaggebend dabei waren meine Eltern, Petra und Dirk, die mich gelehrt haben, Fragen zu stellen bis niemand eine Antwort weiß und Fragen zu beantworten bis niemand mehr fragt. Für die Geduld, das Verständnis, und Toleranz möchte ich meiner gesamten Familie und meinen Freunden danken. Besonders danke ich Daniel, der mich geduldig mit der Wissenschaft geteilt hat, sich viele Laborgeschichten anhören musste und alle meiner wissenschaftlichen Texte Korrektur gelesen hat. Er hat mich motiviert, wenn meine Leidenschaft zur Wissenschaft mehr Leiden als Wissen geschaffen hat. Zu guter Letzt bedanke ich mich bei allen Forscherinnen und Forschern, auf deren Arbeiten ich aufbauen konnte und die maßgeblich zur Naturstoff- und Autophagieforschung durch die Etablierung von Methoden und Aufklärung von Signalwegen beigetragen haben. I Abbreviations 3-MA 3-methyladenine mPGES-1 microsomal prostaglandin E2 5-LO 5-lipo-oxygenase synthase-1 ACAT1 acetyl-CoA acetyltransferase, mTOR Mammalian/mechanistic target of see THIL rapamycin ACON aconitate hydratase mTORC1/2 Mammalian/mechanistic target of ADP Adenosine diphosphate rapamycin complex 1/2 AKT RAC-alpha serine/threonine- NAD(P)H reduced Nicotinamide adenine protein kinase dinucleotide (phosphate) AMP Adenosine monophosphate NBR1 next to BRCA1 gene 1 protein AMPK 5'-AMP-activated protein NDP52 nuclear dot protein 52 kinase NIH National Institutes of Health AP-MS affinity purification prior to NIX BCL-2/adenovirus E1B 19 kDa mass spectrometry analysis protein-interacting protein 3-like ATG autophagy-related NQO1 NAD(P)H dehydrogenase [quinone] ATP Adenosine triphosphate 1, formerly called DT diaphorase BAK BCL-2 antagonist/killer OMA1 Overlapping with the m-AAA BAX BCL-2-associated X protein protease 1 homolog BCL-2 B-cell lymphoma 2 OPA1 Optic atrophy protein 1 Bcl-2-L-13 Bcl-2-like protein 13 OPTN optineurin BRCA1 Breast Cancer 1 p62/SQSTM1 protein of 62 kDa, CALCOCO2 calcium-binding and coiled-coil also Sequestosome-1 domain-containing protein 2, PAINS pan-assay interference compounds see NBR1 PARL presenilin-associated rhomboid-like CCCP carbonyl cyanide m- protease chlorophenyl hydrazone PI phosphatidylinositol CDDP, also CisPt cisplatin PI3K phosphatidylinositol 3-kinase CMA chaperone-mediated PI3P phosphatidylinositol 3-phosphate autophagy PINK1 PTEN-induced putative kinase CPS1 carbamoyl-phosphate protein 1 synthase 1 PTEN phosphatidylinositol 3,4,5- (H)CQ (hydroxy)chloroquine trisphosphate 3-phosphatase DARTS Drug affinity response target PYGB, also bGP glycogen phosphorylase stability RAB1B1 Ras-related protein Rab-1B ER endoplasmic reticulum RB1CC1 RB1-inducible coiled-coil protein 1 ERBB2 Receptor tyrosine-protein ROS reactive oxygen species kinase erbB-2, see HER2 shRNA short/small hairpin ribonucleic acid FKBP12 FK506 binding protein 12 SNAP synaptosomal-associated protein FRB FKBP12-rapamycin binding SNARE soluble N-ethylmaleimide-sensitive- FUNDC1 FUN14 domain-containing factor attachment receptor protein 1 SOD2 mitochondrial superoxide dismutase GABARAP γ-amino-butyric acid receptor- STAT3, Stat3 Signal transducer and activator of associate protein transcription 3 GATE-16 Golgi-associated ATPase TAX1 transient axonal glycoprotein 1 enhancer of 16 kDa TAX1BP1 TAX1-binding protein 1 GFP/RFP green/red fluorescent protein THIL, also ACAT1 Thiamine-monophosphate kinase HER2 human epidermal growth TIM translocase of inner membrane factor receptor 2 t-LiP-MRM targeted limited proteolysis HS71A heat shock 70 kDa protein 1A TOM translocase of outer membrane HS90A heat shock protein HSP 90α vATPase vacuolar ATPase HSC70, hsc70 heat shock-cognate protein of VDAC1 voltage-dependent anion-selective 70 kDa channel protein 1 LC3 Microtubule-associated Vps34 vacuolar protein sorting 34 proteins 1A/1B light chain 3 WIPI WD repeat domain LIR LC3-interacting region phosphoinositide-interacting protein log P octanol-water partition coefficient II Amino acids Amino acid Single letter code Alanine A Cysteine C Aspartic acid D Glutamic acid E Phenylalanine F Glycine G Histidine H Isoleucine I Lysine K Leucine L Methionine M Asparagine N Proline P Glutamine Q Arginine R Serine S Threonine T Valine V Tryptophan W Tyrosine Y III Table of Contents Acknowledgement .................................................................................................................................... I Abbreviations .......................................................................................................................................... II Summary ................................................................................................................................................. 1 Zusammenfassung ................................................................................................................................... 2 1 Introduction ..................................................................................................................................... 3 1.1 Background and scope of this dissertation ............................................................................. 3 1.2 A short history of intracellular waste removal ........................................................................ 4 1.3 Morphology and molecular pathway of autophagy ................................................................ 5 1.4 Mitophagy ............................................................................................................................... 8 1.5 Autophagy and Apoptosis ..................................................................................................... 10 1.6 Autophagy and Cancer .......................................................................................................... 12 1.7 Natural compounds in drug discovery .................................................................................. 14 1.8 Natural compounds as autophagy modulators in cancer ..................................................... 16 2 Aims of this work ........................................................................................................................... 20 3 Summary of publications ............................................................................................................... 21 3.1 Publications within the scope of this dissertation ...............................................................
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    RSC Advances View Article Online PAPER View Journal | View Issue Daldinone derivatives from the mangrove-derived endophytic fungus Annulohypoxylon sp.† Cite this: RSC Adv.,2017,7,5381 ab c d d Yang Liu, Fabian Stuhldreier, Tibor Kurtan,´ Attila Mandi,´ e f c c Sathishkumar Arumugam, Wenhan Lin, Bjorn¨ Stork, Sebastian Wesselborg, Horst Weber,g Birgit Henrich,h Georgios Daletos*a and Peter Proksch*a Two new benzo[j]fluoranthene metabolites, daldinones H, J (1 and 3), and the likewise undescribed artefact, daldinone I (2), along with six known compounds (4–9) were isolated from the endophytic fungus Annulohypoxylon sp. that was obtained from the Mangrove plant Rhizophora racemosa collected in Cameroon. The structures of the new compounds were elucidated by 1D and 2D NMR as well as by HRESIMS and ECD spectra analysis. Co-cultivation of this fungus with the actinomycetes Streptomyces lividans or with Streptomyces coelicolor resulted in an up to 38-fold increase of 1-hydroxy-8- methoxynaphthalene (9), while no significant induction was detected when the fungus was co-cultivated either with Bacillus subtilis or with Bacillus cereus. Compound 2 exhibited strong to moderate Creative Commons Attribution-NonCommercial 3.0 Unported Licence. cytotoxicity against Ramos and Jurkat J16 cells with IC50 values of 6.6 and 14.1 mM, respectively. Received 24th November 2016 Mechanistic studies indicated that compound 2 induces apoptotic cell death caused by induction of Accepted 30th December 2016 intrinsic apoptosis. Moreover, 2 potently blocks autophagy, a potential pro-survival pathway for cancer DOI: 10.1039/c6ra27306h cells. Feeding experiments with 1,8-dihydroxynaphthalene (DHN) led to an enhanced accumulation of www.rsc.org/advances daldinone B (6), which supported the proposed biogenetic pathway.