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
DOI: https://doi.org/10.17192/z2011.0041
URN: urn:nbn:de:hebis:04-z2011-00419
DDC: 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:
Bon-1-cells, Neuroendokriner Tumor, PPAR, Secretogranin, PPAR, Sekretogranin, Bon-1-Zellen, Pioglitazon, HSP 90, HSP 90, 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.

Summary:
Neuroendocrine Tumors still represent a diagnostic as well as therapeutic problem. Thats why further intensive research is necessary to offer patients a better chance of healing. PPARγ-Agonists like Pioglitazone are already used in diabetes-therapy. But there is data that they may also have anti-carcinogenic as well as carcinogenic effects. Therefore, in this work the effect of Pioglitazone on the proteom of Bon-1-cells, a human neuro-endocrine cell line, was examined. Pioglitazone leads to an increased splitting of HSP 90. This is a molecular chaperone that plays a key-role in many cell-signaling-pathways and thus can prevent entering of the cell into apoptosis. Further HSP 90 is involved in developement and maintenance of those features in carcinoma cells, which lead to malignant growth. However, the increased splitting of HSP 90 doesnt lead to a significant decrease in the total amount of HSP 90 with the result that it wasnt possible to detect a regulation of proteins in HSP 90-influenced pathways. It was further shown that treatment of Bon-1-cells with Pioglitazone leads to a reduction of the intracellular amount of CgA and SgII. This effect isnt achieved by decreased expression but by an increased secretion. The same effect was shown by Lankat-Buttgereit et al. in a Bon-1-cell-line transfected with Pdcd4-si-RNA. In both cases the increased secretion appeared to be caused by an increased expression of Proprotein Convertase 1 (PC 1) as well as by an increased activation of Akt regulated by the PI3-Kinase-pathway. Consistent with this data it could be shown that treatment with Pioglitazone of Bon-1-cells leads to a reduction of Pdcd4-levels and consequently to an activation of Akt, to increased expression of PC 1 and as a result to increased secretion of CgA and SgII. CgA serves as a serum-marker for neuroendocrine tumors. PC 1 can be found in increased amounts in different carcinomas. SgII is the proprotein of Secretoneurin (SN) and is processed by PC 1. SN plays a role in neovascularisation induced by hypoxy in ischemic diseases and solid tumors. Increased PC-1-levels may contribute to the anti-diabetic effect of Pioglitazone by amplifying the processing of proinsulin and proglucagone to insulin and glucagon-like-peptide-1. However, the achieved results however give rise to the opinion that the clinical use of Pioglitazone should be reevaluated.

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