Die Inhibition des Transkriptionsfaktors Snail durch PEG und GN25 in Zelllinien des humanen duktalen Adenokarzinoms des Pankreas (SUIT-2/007 und SUIT-2/028)

Hintergrund: Die Gründe für die schlechte Prognose des duktalen Pankreaskarzinoms sind vor allem auch seine Resistenz gegen Chemotherapeutika und seine frühe Metastasierung. Hierbei spielt die epithelial-mesenchymale Transition (EMT) eine entscheidende Rolle, die mit dem Verlust von Zell-Zell-Verbi...

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Bibliographic Details
Main Author: Dengler, Janina
Contributors: Fendrich, Volker (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Language:German
Published: Philipps-Universität Marburg 2018
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Background The major reasons for the fatal prognosis of the ductal pancreatic adenocarcinoma are its chemoresistance and its early metastasis. Thereby the epithelial-to-mesenchymal transition (EMT) plays an important role, which is characterized by the loss of cell-cell-junctions, cell polarity and the expression of E-Cadherin. A crucial mediator of EMT is the transcription factor Snail, which represses the expression of E-Cadherin by multiple pathways. Unfortunately, therapeutic strategies for inhibition of Snail are barely available. In this study we examined the in vitro inhibition of Snail by PEG and GN25 in the human pancreatic cancer cell lines SUIT-2/007 and SUIT-2/028. Materials and methods For our research we employed subcell lines of SUIT-2, SUIT-2/007 (cell line with high metastatic potential) and SUIT-2/028 (cell line with poor metastatic potential) which were cultured at RPMI/10% FBS. After assessing the required number of cells, the cell lines were incubated with the inhibitors PEG and GN25 over 24h, 72h and 144h with ascending concentrations (PEG: 5% ans 10%; GN25: 0,5µM, 1µM, 2µM, 4µM, 5µM, 6µM, 8µM, 10µM). After the appropriate period of incubation cell vitality has been measured via MTT assay at the ELISA reader at 570nm and 630nm. Results The inhibition of the cell lines with PEG showed a dose dependent growth repression of both cell lines, whereupon significant reduction of viable cells could be seen only after 144 hours of incubation (p<0,001). This effect was comparable between the two different cell lines. Even more obvious was the inhibition of the cell lines seen by treatment with GN25. There we could observe a significant repression of growth after 72 hours of incubation, which was still present after 144 hours (p<0,001). Moreover, there was a highly significant decrease of viable cells starting from 5µM (p<0,05). This effect was comparable between the two cell lines, too. Conclusion PEG and GN25 showed a significant dose dependent inhibition of Snail at pancreatic cancer cells in vitro, whereupon GN25 induced repression of cell growth occured faster and in lower doses compared to the inhibition by PEG. PEG and particularly GN25 represent potential new approaches for the therapy of metastatic pancreatic cancer.