Die Rolle der Glutathion S-Transferase Omega 1 in einem nativen und Cisplatin-resistenten Keimzelltumor

by Fatih Yüksel
Doctoral thesis
Date of Examination:2025-10-28
Date of issue:2025-10-13
Advisor:Prof. Dr. Felix Bremmer
Referee:Prof. Dr. Felix Bremmer
Referee:PD Dr. Anja Uhmann
Persistent Address: http://dx.doi.org/10.53846/goediss-11546

 

 

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Abstract

English

Testicular germ cell tumors represent the most common malignant disease in young men between the ages of 20 and 40. Histologically, they are classified according to the WHO classification into different subtypes, with a clinically relevant distinction made between seminomas and non-seminomas for therapeutic purposes. Since the introduction of cisplatin-based high-dose chemotherapy, excellent cure rates have been achieved. Nevertheless, a clinically relevant proportion of patients does not respond adequately to treatment due to cisplatin resistance. Currently, reliable biomarkers for the early detection of such resistance as well as for the development of novel therapeutic approaches are lacking. Glutathione S-transferase omega 1 (GSTO1), an isoform of the glutathione S-transferases, is involved in various biochemical processes of biotransformation. Increased expression of GSTO1 has been associated with several pathological processes, including tumorigenesis and drug resistance. In the present study, GSTO1 was analyzed using mass spectrometry-based proteomics in both cisplatin-sensitive and cisplatin-resistant cell lines. GSTO1 was found to be upregulated in the resistant cell line, suggesting a possible functional role in the development of cisplatin resistance. To further explore this, a GSTO1 knockdown was performed in order to investigate its effects on cellular activity and relevant signaling pathways. Following cisplatin exposure, a dose-dependent reduction in metabolic activity was observed, with the resistant cell line showing a diminished response. Control experiments with non-specific RNA confirmed the specificity of these effects. In addition, GSTO1 knockdown led to alterations in key signaling pathways such as JNK, AKT, and ERK, which play crucial roles in the regulation of proliferation and apoptosis. In summary, the results of our experimental model suggest that GSTO1 contributes to the establishment of cellular survival mechanisms. Enhanced activation of survival signaling as well as stabilization of resistance support a potential role of GSTO1 as a biomarker. This may open up novel therapeutic avenues for overcoming cisplatin resistance in testicular germ cell tumors.
Keywords: Testicular germ cell tumors (TGCTs); Seminoma / Non-seminoma; Cisplatin resistance; Biomarkers; Glutathione S-transferase omega 1 (GSTO1); Proteomics / Mass spectrometry; RNA knockdown; Signal transduction (JNK, AKT, ERK pathways); Apoptosis and proliferation; Therapeutic targets