Publikationsserver der Universitätsbibliothek Marburg
Titel:Transkriptionsregulation der Pyruvatdehydrogenase-Kinase 4 (PDK4), einem zentralen Schalter des Glukosestoffwechsels, durch Zelladhäsion und onkogene Signalwege beim humanen Ovarialkarzinom
Autor:Schnitzer, Evelyn
Weitere Beteiligte: Müller-Brüsselbach, Sabine (PD Dr.)
Veröffentlicht:2016
URI:https://archiv.ub.uni-marburg.de/diss/z2016/0601
URN: urn:nbn:de:hebis:04-z2016-06015
DOI: https://doi.org/10.17192/z2016.0601
DDC:610 Medizin
Titel (trans.):Transcriptional regulation of pyruvate dehydrogenase kinase 4 (PDK4), a key regulator of glucose metabolism, via cell adhesion and oncogenic signaling in human ovarian carcinoma
Publikationsdatum:2016-09-08
Lizenz:https://creativecommons.org/licenses/by-nc-sa/4.0

Dokument

Schlagwörter:
Life sciences, Pyruvatdehydrogenase-Kinase 4, Zelladhäsion, Eierstockkrebs, Signaltransduktion, Glucosestoffwechsel, Biowissenschaften, Transcriptional regulation, Genregulation

Zusammenfassung:
Das Ovarialkarzinom ist die gynäkologische Krebserkrankung mit der höchsten Letalität, was vor allem durch die passive Metastasierung über den Peritonealraum bedingt ist. Dabei breiten sich Tumorzellen als Einzelzellen oder mehrzellige Sphäroide über die Peritonealflüssigkeit aus, um an anderer Stelle Metastasen auszubilden. Der damit einhergehende Adhärenzverlust dieser Zellen ist demnach von großer klinischer Relevanz und bedarf weiterer funktioneller Analysen. Im Rahmen dieser Arbeit konnte mit PDK4 erstmals ein Gen in primären humanen Ovarialkarzinomzellen und in der Modellzelllinie SKOV-3 identifiziert werden, dessen Expression stark von Adhärenz und Adhärenzverlust beeinflusst wird. Die mit dem Adhärenzverlust einhergehende Induktion scheint mit dem glykolytischen Metabolismus dieser Zellen funktionell in Verbindung zu stehen, im Einklang mit der zentralen Rolle von PDKs als negative Regulatoren der Pyruvatdehydrogenase und somit der Energiegewinnung aus Glukose durch oxidative Phosphorylierung. Eine detaillierte Untersuchung der adhärenzvermittelten PDK4-Regulation zeigte, dass Interaktionen zwischen Komponenten der Extrazellulärmatrix und Integrinen dafür verantwortlich sind. Der weitere Fokus der vorliegenden Arbeit lag auf der detaillierten mechanistischen Aufklärung dieser transkriptionellen Kontrolle und die damit verbundene Identifizierung der verantwortlichen Signalwege anhand der Modellzelllinie SKOV-3. Hierzu wurde nach pharmakologischer Modulation bestimmter Signalwege oder einer RNAi-vermittelten Inhibition spezifischer Signalproteine die Phosphorylierung kritischer Signalkomponenten, Chromatinbindung und Regulation von PDK4 untersucht. Die hierbei erzielten Ergebnisse deuten auf eine Kooperation mehrerer Signalwege bei der Regulation des PDK4-Gens durch Adhärenzverlust hin. Hierzu zählen der SRC-PI3K-AKT-Signalweg, die GSK3-β-Catenin-Signalkaskade, der Estrogenrezeptor, der Transkriptionsfaktor C/EBPβ und Umstrukturierungen des Aktinzytoskeletts. Über die adhärenzvermittelte PDK4-Regulation hinaus liefern die Ergebnisse dieser Arbeit ein Bild zur Transkriptionsregulation des PDK4-Gens durch tumorbiologisch relevante Signale im humanen Ovarialkarzinom. So führen die Aktivierung des Adenylylcyclase-cAMP-PKA-Signalwegs, die Inhibition des SRC-PI3K-AKT-Signalwegs sowie Estrogen, Glukokortikoid und Zell-Zell-Kontakte zu einer Induktion der PDK4-Expression. Die komplexe Regulation von PDK4, insbesondere auch durch onkogene Signalwege, und die zentrale Funktion im Glukosemetabolismus unterstreichen die essentielle Rolle von PDK4 im Tumormetabolismus und weisen auf PDK4 als mögliches therapeutisches Ziel bei der Behandlung des Ovarialkarzinoms hin.

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