Die Wirkung von Pioglitazon auf das Proteom einer humanen neuroendokrinen Pankreaskarzinom-Zelllinie

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...

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Bibliographic Details
Main Author: Müller, Sabine
Contributors: Lankat-Buttgereit, Brigitte (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Language:German
Published: Philipps-Universität Marburg 2011
Subjects:
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Table of Contents: 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.