Publikationsserver der Universitätsbibliothek Marburg

Titel:Identifizierung von Stoffwechselwegen in humanen Ovarialkarzinomzellen mit potentiell therapeutischer Relevanz
Autor:Obert, Julia
Weitere Beteiligte: Müller, Rolf (Prof Dr.)
Veröffentlicht:2017
URI:https://archiv.ub.uni-marburg.de/diss/z2017/0200
URN: urn:nbn:de:hebis:04-z2017-02002
DOI: https://doi.org/10.17192/z2017.0200
DDC: Medizin, Gesundheit
Titel(trans.):Identification of metabolic pathways in human ovarian cancer cells with potential therapeutic relevance
Publikationsdatum:2017-03-16
Lizenz:https://creativecommons.org/licenses/by/4.0

Dokument

Schlagwörter:
Eierstockkrebs, ECAR, proliferation, Intermediärstoffwechsel, ovarian cancer, Proliferation, metabolism, OCR, Metabolismus

Zusammenfassung:
Ein typisches Merkmal von Tumorzellen ist ihr veränderter Intermediärstoffwechsel. Tumor¬zellen sind häufig gekennzeichnet durch eine gesteigerte Glukoseaufnahme sowie die Bildung von Laktat auch in Anwesenheit von Sauerstoff (aerobe Glykolyse, "Warburg-Effekt"). Als weitere verstärkt ablaufende Stoffwechselwege rücken zunehmend der Abbau von Glutamin als anaplerotische Reaktion des Citratzyklus ("Glutaminolyse"), die de novo Fettsäuresynthese und der Fettsäureabbau über die β-Oxidation in den Mittelpunkt der Forschung. Die Inhibition dieser Stoffwechselwege könnte eine geeignete Angriffsstelle für künftige Krebstherapien sein. Das Ovarialkarzinom ist die gynäkologische Krebserkrankung mit der höchsten Letalität und weist häufig die Bildung von Aszites als besonderes Charakteristikum auf. Die Isolierung primärer Tumorzellen aus Aszites bietet eine einzigartige Möglichkeit zur Erforschung metabolischer Aberrationen in dieser Tumorentität. Ziel dieser Arbeit war die Identifizierung tumorspezifischer Stoffwechselwege als mögliche Angriffspunkte neuer Therapieansätze. Hierzu wurden patientenabgeleitete Ovarialkarzinomzellen im Vergleich zu einer Reihe etablierter Tumorzelllinien und der nicht-transformierten Brustepithelzelllinie MCF 10A eingesetzt. Voraussetzung dafür war die genaue Charakterisierung des metabolischen Phänotyps mit Hilfe von Expressionsanalysen und "metabolic profiling" mittels des Seahorse XFe Analyzers. Dafür wurden die metabolischen Parameter OCR (oxygen consumption rate) und ECAR (extracellular acidification rate) sowie die entsprechenden Kapazitäten unter Normalbedingungen und unter Anwendung von metabolischem Druck, vor allem durch den Einsatz von metabolischen Inhibitoren, gemessen. Im Zuge dieser Arbeit fiel eine Besonderheit im Stoffwechsel der Ovarialkarzinomzelllinie SKOV-3 auf. Die ATP-Produktion aus Glukose mittels oxidativer Phosphorylierung (OXPHOS) ist in diesen Zellen blockiert. Vermutet wurde zunächst ein Defekt im Citratzyklus. Dies ist jedoch nicht kompatibel mit dem Befund, dass SKOV-3 Zellen die ATP-Gewinnung mittels OXPHOS über einen längeren Zeitraum aufrechterhalten können. Deshalb wurde ein "fatty acid cycle" (FAC) als alternativer Stoffwechselweg postuliert, der aus dem zyklischen Auf- und Abbau von Fettsäuren besteht. Die Vorteile des FAC für die Tumorzelle könnten in einer Unabhängigkeit von externer Substratzufuhr bei einer geleichzeitig gesteigerten anabolen Kapazität aufgrund der Verlagerung des Glukosestoffwechsels in Richtung Pentosephosphatweg sein. Aufgrund der potentiellen Vorteile des FAC für proliferierende Zellen ist es wahrscheinlich, dass dieser Zyklus auch in anderen Zellen operativ ist. Die Ursache für die Besonderheiten des SKOV-3 Stoffwechsels ist möglicherweise ein verminderter Transport von Pyruvat in die Mitochondrienmatrix aufgrund einer verringerten Expression des Gens für den Mitochondrial Pyruvate Carrier 1 (MPC1). Ein weiterer wichtiger Befund war die Feststellung einer gesteigerten aeroben Glykolyse und β-Oxidation in allen patientenabgeleiteten Ovarialkarzinomzellen. Durch den Einsatz von Inhibitoren für Tumorzellen relevante Stoffwechselwege wurde die Möglichkeit einer Interferenz mit der Proliferation bzw. dem Überleben dieser Zellen mit Hilfe des xCELLigence RTCA untersucht. Dabei zeigte sich, dass einzelne Inhibitoren nur in exzessiv hohen Konzentrationen die Proliferation (wahrscheinlich unspezifisch) hemmten, dass aber die Kombination verschiedener Stoffwechselmodulatoren in Konzentrationen, in denen sie als einzelner Wirkstoff wirkungslos waren, zu deutlichen synergistischen Effekten führte. Vor allem die Kombination von Oxamat (Laktat-Dehydrogenase-Inhibitor) mit den Inhibitoren DCA (Inhibitor der Pyruvat-Dehydrogenase-Kinasen; PDKs), AOA (Inhibitor der Aspartat-Transaminase und damit des Malat-Aspartat-Shuttles) sowie SB204990 (Inhibitor der ATP-Citrat-Lyase) verursachte eine deutliche Proliferationsinhibition, bis hin zum Absterben der Zellen. Dennoch unterscheiden sich Ovarialkarzinomzellen von verschiedenen Patientinnen zum Teil deutlich hinsichtlich ihres Metabolismus bzw. der Auswirkungen von Inhibitoren auf die Proliferation. Beispiele hierfür sind Unterschiede bei (i) der Nutzung von Glutamin und Pyruvat als alleinigem Substrat, (ii) der Abhängigkeit von PDKs, Laktat-Dehydrogenase und Aspartat-Transaminase (iii) der Korrelation metabolischer Reaktionen auf Inhibitoren mit Effekten auf die Proliferation. Dies zeigt, dass eine potentielle Anwendung metabolischer Inhibitoren eine personalisierte Tumordiagnostik notwendig macht, um individuell optimale Kombinationen von Wirkstoffen zu identifizieren. Zudem könnte die Untersuchung dieser Hemmstoffe in Kombination mit Chemotherapeutika oder Modulatoren von Signalwegen ggf. zu optimierten Therapiekonzepten führen.

Summary:
A characteristic feature of tumor cells is their altered intermediary metabolism. Tumor cells frequently exhibit increased glucose uptake and lactate production even in the presence of oxygen (aerobic glycolysis, "Warburg effect"). Other metabolic pathways activated in tumor cells, including the degradation of glutamin as an anaplerotic reaction of the citric acid cycle ("glumaminolysis"), de novo fatty acid synthesis and fatty acid degradation via β-oxidation also have attracted particular attention. These altered metabolic pathways represent promising potential pharmacologic targets for cancer therapy . Ovarian cancer is the most lethal of all gynaecologic malignancies with the development of ascites in the peritoneal cavity as a characteristic feature. The isolation of primary cancer cells from ascites provides a unique opportunity to investigate metabolic aberrations in this tumor entity. The aim of this study was the identification of tumor-specific metabolic pathways as potential targets for new therapeutic approaches. For this purpose, patient-derived ovarian carcinoma cells were analyzed in comparison to a number of established tumor cell lines and the non-transformed breast epithelial cell line MCF-10A. A prerequisite for this study was the characterization of the metabolic phenotypes by expression analysis and "metabolic profiling" using the Seahorse XFe analyzer. Towards this goal, the metabolic parameters OCR (oxygen consumption rate) and ECAR (extracellular acidification rate) as well as the corresponding metabolic capacities were measured under normal conditions and metabolic pressure, mainly induced by metabolic inhibitors. This work revealed a specific metabolic feature of the ovarian carcinoma cell line SKOV-3. ATP production from glucose by oxidative phosphorylation (OXPHOS) is blocked in these cells. Initially, this was hypothesized to be caused by a defect in TCA-cycle. However, this hypothesis is not compatible with the finding that SKOV-3 cells are able to sustain ATP recovery via OXPHOS over long periods of time. Therefore, a "fatty acid cycle" (FAC) was postulated as an alternative metabolic pathway. This pathway consists of the cyclic synthesis and degradation of fatty acids. The advantages of the FAC could be independence of external supply of substrates and increased anabolic capacity due to a shift of glucose metabolism towards pentose phosphate pathway. Due to the advantages of the FAC for proliferating cells, it is likely that this cycle is also operative in a variety of other cells. The reason for the abnormal SKOV-3 metabolism was in the end localised as a defect in pyruvate transport into the mitochondrial matrix, which is due to a reduced expression of Mitochondrial Pyruvate Carrier 1 gene (MPC1). Another important result was the finding of increased aerobic glycolysis and β-oxidation in all patient-derived ovarian carcinoma cells. By using inhibitors of tumor relevant metabolic pathways, the potential to interfere with the proliferation or survival of these cells was examined using the xCELLigence RTCA. It was shown that single inhibitors were able to reduce proliferation (probably unspecifically) only at excessive concentrations, but that the combination of different metabolic modulators at concentrations ineffective on their own resulted in significant synergistic effects. Especially the combination of Oxamate (lactate dehydrogenase inhibitor) with the inhibitors DCA (inhibitor of pyruvate dehydrogenase kinases; PDKs), AOA (inhibitor of aspartate transaminase and thus of the malate aspartate shuttle) and SB204990 (inhibitor of ATP citrate lyase) caused a distinct proliferation inhibition, including cell death. Nevertheless ovarian carcinoma cells from different patients differ in part substantially with respect to their metabolism and the anti-proliferative effects of inhibitors. Examples are differences in (i) the utilization of glutamine and pyruvate as the sole substrate, (ii) the dependence of PDKs, lactate dehydrogenase and aspartate transaminase, and (iii) the correlation of metabolic responses to inhibitors with anti-proliferative effects. This demonstrates that the potential application of metabolic inhibitors necessitates personalized tumor diagnostics to identify individually optimal combinations of drugs. Furthermore, the investigation of these inhibitors in combination with chemotherapeutic agents or modulators of signaling pathways could possibly lead to optimized therapeutic concepts.

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