Mechanismen der Tumorsuppression und Resistenzüberwindung einer therapeutischen GSK-3β- Inhibition im Pankreaskarzinom

by Lioba Augustin
Doctoral thesis
Date of Examination:2025-02-24
Date of issue:2025-02-17
Advisor:Prof. Dr. Volker Ellenrieder
Referee:Prof. Dr. Volker Ellenrieder
Referee:Prof. Dr. Holger Bastians
Persistent Address: http://dx.doi.org/10.53846/goediss-11076

 

 

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Abstract

English

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of human cancer with a five-year survival of only 11%. Recent studies have shown that PDAC results from a successive accumulation of different genetic and epigenetic mutations and therefore development of different subtypes. Because of its complexity in origin and thus a stagnant progress in therapy, the prognosis remains poor. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine kinase which regulates several cellular functions and is highly expressed in different pancreatic cancer cell lines. It is known as a key enzyme in glycogen metabolism as well as a modifier of structural proteins and transcription factors. Systemic knock-out of GSK-3β gene in mice leads to embryonic lethality through hepatocyte apoptosis and liver degeneration. In various tumor types GSK-3β is a potential therapeutic target whose inhibition leads to a suppressed tumor cell viability. In the recent results we were able to show, that a pharmacological inhibition of GSK-3β in murine and human malignant cell lines leads to cell cycle arrest and a significant decrease in proliferation. Depending on cell line and way of inhibition, there were several effects on target gene expression, histone modification, histone demethylases, cell cycle and proliferation.
Keywords: Glycogen Synthase Kinase-3 Beta