Publikationsserver der Universitätsbibliothek Marburg

Titel:Die Wirkung von Pioglitazon auf das Proteom einer humanen neuroendokrinen Pankreaskarzinom-Zelllinie
Autor:Müller, Sabine
Weitere Beteiligte: Lankat-Buttgereit, Brigitte (Prof. Dr.)
Veröffentlicht:2011
URI:https://archiv.ub.uni-marburg.de/diss/z2011/0041
URN: urn:nbn:de:hebis:04-z2011-00419
DOI: https://doi.org/10.17192/z2011.0041
DDC:610 Medizin
Titel (trans.):Impact of Pioglitazone-treatment on the proteom of a human neuroendocrine pancreatic carcinoma cell line
Publikationsdatum:2011-03-03
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
HSP 90, PPAR, Sekretogranin, Pioglitazon, PPAR, Bon-1-cells, Bon-1-Zellen, HSP 90, Secretogranin, Neuroendokriner Tumor, Chromogranin A, Neurosekretorische Zelle

Zusammenfassung:
Neuroendokrine Tumore stellen auch heute noch sowohl ein diagnostisches als auch therapeutisches Problem dar, weswegen weiterhin intensive Forschung notwendig ist, um Patienten mit dieser Erkrankung eine höhere Chance auf Heilung zu bieten. PPARγ-Agonisten wie Pioglitazon werden klinisch bereits in der Diabetes-Therapie eingesetzt. Es gibt allerdings Daten, die sowohl auf antikanzerogene als auch auf kanzerogene Effekte dieser Wirkstoffgruppe hinweisen. Daher wurde in dieser Arbeit die Wirkung von Pioglitazon auf das Proteom von Bon-1-Zellen untersucht, einer humanen neuroendokrinen Pankreaskarzinom-Zelllinie. Es zeigte sich, dass Pioglitazon-Behandlung in Bon-1-Zellen zu einer vermehrten Spaltung von HSP 90 führt. HSP 90 ist ein molekulares Chaperon, das eine Schlüsselrolle in vielen Zell-Signalwegen spielt und so den Eintritt der Zelle in die Apoptose verhindern kann. Ebenso ist es maßgeblich an der Entwicklung und Aufrechterhaltung derjenigen Eigenschaften von Tumorzellen beteiligt, die zu malignem Wachstum führen. Es musste jedoch festgestellt werden, dass die vermehrte Spaltung von HSP 90 anscheinend nicht zu einer signifikanten Abnahme der Gesamtmenge an HSP 90 führt, und deswegen keine Regulation von Proteinen in HSP-90-beeinflussten Signalwegen nachgewiesen werden konnte. Weiterhin konnte gezeigt werden, dass eine Inkubation von Bon-1-Zellen mit Pioglitazon zu einer Verminderung der intrazellulären Menge an CgA und SgII führt. Dieser Effekt wird nicht durch eine verminderte Expression, sondern durch eine verstärkte Sekretion erzielt. Der gleiche Effekt wurde durch Lankat-Buttgereit et al. in einer mit Pdcd4-si-RNA-transfizierten Bon-1-Zelllinie nachgewiesen. In beiden Fällem schien die gesteigerte Sekretion sowohl durch eine vermehrte Expression der Proprotein-Convertase 1 (PC1) als auch durch eine vermehrte Aktivierung der Kinase Akt, reguliert über den PI3-Kinase-Weg, bedingt zu sein. Übereinstimmend hiermit wurde in dieser Arbeit nachgewiesen, dass Pioglitazon in Bon-1-Zellen zu erniedrigten Pdcd4-Spiegeln und infolgedessen zur Aktivierung von Akt, zu gesteigerter PC1-Expression und hierdurch zu vermehrter CgA- und SgII-Sekretion führt. CgA dient als Serummarker für neuroendokrine Tumore und PC1 ist in erhöhten Mengen in verschiedenen Tumorarten zu finden. SgII ist das Vorläuferprotein von Secretoneurin (SN) und wird durch PC1 zu diesem prozessiert. SN spielt eine Rolle bei der Hypoxie-induzierten Neovaskularisation in ischämischen Erkrankungen und soliden Tumoren. Erhöhte PC1-Spiegel unter Pioglitazon-Behandlung mögen jedoch auch zur antidiabetischen Wirkung von Pioglitazon beitragen, indem es zu einer vermehrten Prozessierung von Proinsulin und Proglucagon zu Insulin und dem insulinotrop wirkenden Glucagon-like-Peptide-1 (GLP-1) kommt. Die erzielten Ergebnisse geben weiteren Anlass zu der Auffassung, dass der klinische Einsatz von Pioglitazon erneut reevaluiert werden sollte.

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